Zfhx3-mediated genetic ablation of the SCN abolishes light entrainable circadian activity while sparing food anticipatory activity.

Circadian rhythms persist in almost all organisms and are crucial for maintaining appropriate timing in physiology and behaviour. Here, we describe a mouse mutant where the central mammalian pacemaker, the suprachiasmatic nucleus (SCN), has been genetically ablated by conditional deletion of the transcription factor Zfhx3 in the developing hypothalamus. Mutants were arrhythmic over the light-dark cycle and in constant darkness. Moreover, rhythms of metabolic parameters were ablated in vivo although molecular oscillations in the liver maintained some rhythmicity. Despite disruptions to SCN cell identity and circuitry, mutants could still anticipate food availability, yet other zeitgebers - including social cues from cage-mates - were ineffective in restoring rhythmicity although activity levels in mutants were altered. This work highlights a critical role for Zfhx3 in the development of a functional SCN, while its genetic ablation further defines the contribution of SCN circuitry in orchestrating physiological and behavioral responses to environmental signals.

Plastic physicians: The surgical salamanders of the COVID-19 pandemic.

At the time of writing, coronavirus disease-2019 (COVID-19) has affected 6.42 million people globally and over 380,000 deaths, with the United Kingdom now having the highest death rate in Europe. The plastic surgery department at Leeds Teaching Hospitals put necessary steps in place to maintain an excellent urgent elective and acute service whilst also managing COVID-positive medical patients in the ward. We describe the structures and pathways implemented together with complex decision-making, which has allowed us to respond early and effectively. We hope these lessons will prove a useful tool as we look to open conversations around the recovery of normal activity.

The effects of microchipping C57BL/6N mice on standard phenotyping tests.

The C57BL/6N inbred lines of mice are widely used in genetic research. They are particularly favoured in large scale studies such as the International Mouse Phenotyping Consortium (IMPC), where C57BL/6N mice are genetically altered to generate a collection of null alleles (currently more than 8500 null alleles have been generated). In this project, mice carrying null alleles are subjected to a pipeline of broad-based phenotyping tests to produce wide ranging phenotyping data on each model. We have previously described the development of a Home Cage Analysis system that automatically tracks the activity of group housed mice from a microchip inserted in the groin. This platform allows assessment of multiple biologically relevant phenotypes over long periods of time without experimenter interference, and therefore is particularly suited for high through-put studies. To investigate the impact of microchips on other tests carried out in the IMPC pipeline, we inserted microchips in 12 male and 12 female C57BL/6Ntac mice at seven weeks of age. Starting at nine weeks of age these mice underwent standard phenotyping tests, concurrently with 20 unchipped C57BL/6Ntac mice (10 females, 10 males). Tissues from a subset of the microchipped mice (six males and six females), chosen at random, were also sent for histopathological examination at the end of the phenotyping pipeline. No significant impact of insertion of microchip was observed in any of the phenotyping tests apart from bone mineral density measurement at DEXA due to the nature of the microchip. We therefore recommend that the microchip be inserted during the DEXA procedure, after the measurement is taken but before the mouse has recovered from the anaesthetic. This would avoid multiple anaesthetic exposures and prevent the potential variability in DEXA analysis output.

Changes in mitochondrial function are pivotal in neurodegenerative and psychiatric disorders: how important is BDNF?

The brain is at the very limit of its energy supply and has evolved specific means of adapting function to energy supply, of which mitochondria form a crucial link. Neurotrophic and inflammatory processes may not only have opposite effects on neuroplasticity, but also involve opposite effects on mitochondrial oxidative phosphorylation and glycolytic processes, respectively, modulated by stress and glucocorticoids, which also have marked effects on mood. Neurodegenerative processes show marked disorders in oxidative metabolism in key brain areas, sometimes decades before symptoms appear (Parkinson's and Alzheimer's diseases). We argue that brain-derived neurotrophic factor couples activity to changes in respiratory efficiency and these effects may be opposed by inflammatory cytokines, a key factor in neurodegenerative processes.

Sevoflurane and propofol depolarize mitochondria in rat and human cerebrocortical synaptosomes by different mechanisms.

BACKGROUND AND OBJECTIVES: The mitochondrial membrane potential drives the main functions of the mitochondria. Sevoflurane depolarizes neural mitochondria. There is still, however, limited information concerning the effect of anaesthetics on neural mitochondria in humans. The effect of sevoflurane and propofol on the intracellular Ca(2+) concentration [Ca(2+)](i) and the mitochondrial membrane potential (DeltaPsi(m)) was therefore compared in rat and human synaptosomes, and the changes were related to interventions in the electron transport chain. METHODS: Synaptosomes from rat and human cerebral cortex were loaded with the fluorescent probes fura-2 ([Ca(2+)](i)) and JC-1 (DeltaPsi(m)) before exposure to sevoflurane 1 and 2 minimum alveolar concentration (MAC), and propofol 30 and 100 microM. The effect on the electron transport chain was investigated by blocking complex V. RESULTS: Sevoflurane and propofol decreased DeltaPsi(m) in rat synaptosomes in a dose-dependent manner, and to the same extent by equipotent doses. Inhibition of complex V enhanced the depolarizing effect of sevoflurane 2 MAC, but not of propofol 100 microM. Neither sevoflurane nor propofol affected [Ca(2+)](i) significantly. Sevoflurane and propofol decreased DeltaPsi(m) in human synaptosomes to the same extent as in the rat experiments. CONCLUSIONS: Sevoflurane and propofol at equipotent doses depolarize the mitochondria in rat and human nerve terminals to the same extent. The depolarizing effect of propofol on Psi(m) was more rapid in onset than that of sevoflurane. Whereas sevoflurane inhibits the respiratory chain sufficiently to cause ATP synthase reversal, the depolarizing effect of propofol seems to be related to inhibition of the respiratory chain from complex I to V.

Mercury sensitisation: review, relevance and a clinical report.

Eczematous eruptions may be produced through topical contact with mercury and by systemic absorption in mercury sensitive individuals. Mercury is considered a weak sensitiser and contact with mercury salts such as chloride or ammonium chloride may cause hypersensitivity leading to contact dermatitis or Coomb's Type IV hypersensitivity reactions. The typical manifestation is an urticarial or erythematous rash, and pruritus on the face and flexural aspects of limbs, followed by progression to dermatitis. True allergy to mercury is rare but is more common in females. Exposure to mercury vapour produced in operating rooms is the main concern for dentists. Every effort should be made to avoid contact with mercury vapour if possible by using barrier techniques, reducing the temperature of the operating room and of the amalgam restoration. Air conditioning and proper ventilation of the operating room, the use of coolant sprays, good suction and proper handling of amalgam waste is recommended. Various reports show the use of MELISA (memory lymphocyte immunostimulation assay) and patch tests in determining mercury sensitivity. Topical application of glucocorticoids and dimethisone is helpful.

Recurrent carpal tunnel syndrome in a child due to fibrolipomatous hamartoma of the median nerve successfully treated by limited excision and decompression.

We present a case of recurrent carpal tunnel syndrome in a child caused by fibrolipomatous hamartoma of the median nerve which was successfully treated by limited excision of the fibrolipomatous tissue and decompression.

Volatile anaesthetics depolarize neural mitochondria by inhibiton of the electron transport chain.

BACKGROUND: The mitochondrial membrane potential (DeltaPsim) controls the generation of adenosine triphosphate (ATP) and reactive oxygen species, and sequesteration of intracellular Ca2+[Ca2+]i. Clinical concentrations of sevoflurane affect the DeltaPsim in neural mitochondria, but the mechanisms remain elusive. The aim of the present study was to compare the effect of isoflurane and sevoflurane on DeltaPsim in rat pre-synaptic terminals (synaptosomes), and to investigate whether these agents affect DeltaPsim by inhibiting the respiratory chain. METHODS: Synaptosomes were loaded with the fluorescent probes JC-1 (DeltaPsim) and Fura-2 ([Ca2+]i) and exposed to isoflurane or sevoflurane. The effect of the anaesthetics on the electron transport chain was investigated by blocking complex I and complex V. RESULTS: Isoflurane 1 and 2 minimum alveolar concentration (MAC) decreased the normalized JC-1 ratio from 0.92 +/- 0.03 in control to 0.86 +/- 0.02 and 0.81 +/- 0.01, respectively, reflecting a depolarization of the mitochondrial membrane (n = 9). Isoflurane 2 MAC increased [Ca2+]i. In Ca2+-depleted medium, isoflurane still decreased DeltaPsim while [Ca2+]i remained unaltered. The effect of isoflurane was more pronounced than for sevoflurane. Blocking complex V of the respiratory chain enhanced the isoflurane- and sevoflurane-induced mitochondrial depolarization, whereas blocking complex I and V decreased DeltaPsim to the same extent in control, isoflurane and sevoflurane experiments. CONCLUSIONS: Isoflurane and sevoflurane may act as metabolic inhibitors by depolarizing pre-synaptic mitochondria through inhibition of the electron transport chain, although isoflurane seems to inhibit mitochondrial function more significantly than sevoflurane. Both agents inhibit the respiratory chain sufficiently to cause ATP synthase reversal.

Sevoflurane depolarizes pre-synaptic mitochondria in the central nervous system.

BACKGROUND: Volatile anaesthetics protect the heart from ischaemic injury by activating mitochondrial signalling pathways. The aim of this study was to test whether sevoflurane, which is increasingly used in neuroanaesthesia, affects mitochondrial function in the central nervous system by altering the mitochondrial membrane potential (DeltaPsi(m)). METHODS: In order to correlate free cytosolic Ca(2+) ([Ca(2+)](i)) and DeltaPsi(m), rat neural presynaptic terminals (synaptosomes) were loaded with the fluorescent probes fura-2 and JC-1. During sevoflurane exposure, 4-aminopyridine (4-AP) 500 micro M to induce pre-synaptic membrane depolarization or carbonylcyanide-p-(trifluoromethoxy)-phenylhydrazone (FCCP) 1 micro M to induce maximum mitochondrial depolarization was added. In order to block mitochondrial ATP-regulated K(+)-channels (mitoK(ATP)), the antagonist 5-hydroxydecanoate (5-HD) 500 micro M was added. RESULTS: In Ca(2+)-containing medium, both sevoflurane 1 and 2 MAC gradually decreased the normalized JC-1 ratio from 0.96 +/- 0.01 in control to 0.92 +/- 0.01 and 0.89 +/- 0.01, representing a depolarization of DeltaPsi(m) (n = 9, P < 0.05). Sevoflurane 2 MAC increased [Ca(2+)](i). In Ca(2+)-depleted medium, sevoflurane 1 and 2 MAC depolarized DeltaPsi(m), while [Ca(2+)](i) remained unaltered. Sevoflurane 2 MAC attenuated the 4-AP-induced depolarization of DeltaPsi(m). When mitoK(ATP) was blocked, the sevoflurane-induced depolarization of DeltaPsi(m) was attenuated, but not blocked. The depolarizing effect of sevoflurane on DeltaPsi(m) compared with FCCP was calculated to 13.2 +/- 1.3% in Ca(2+)-containing and 15.1 +/- 1.2% in Ca(2+)-depleted medium (n = 7). CONCLUSIONS: Sevoflurane depolarizes DeltaPsi(m) in rat synaptosomes, and the effect is not dependent on Ca(2+)-influx to the cytosol. Opening of mitoK(ATP) is partly responsible for the depolarizing effect of sevoflurane.

Morphological determinants of femoral strength in growth hormone-deficient transgenic growth-retarded (Tgr) rats.

UNLABELLED: The extent to which childhood GHD affects adult fracture risk is unclear. We measured femoral strength in adult transgenic growth-retarded rats as a model of GHD. Long-term, moderate GHD was accompanied by endocrine and morphometric changes consistent with a significant reduction in femoral strength. INTRODUCTION: Childhood growth hormone deficiency (GHD) is associated with osteopenia, but little is known about its effects on subsequent adult bone strength and fracture risk. MATERIALS AND METHODS: We have therefore measured femoral strength (failure load measured by three-point bending) in a new model of moderate GHD, the transgenic growth-retarded (Tgr) rat at 15, 22-23, and 52 weeks of age, and have quantified potential morphological and endocrine determinants of bone strength. RESULTS: Skeletal growth retardation in Tgr rats was accompanied by a sustained reduction in the anterior-posterior diameter of the femoral cortex, whereas mid-diaphyseal cortical wall thicknesses were largely unaltered. Total femoral strength was significantly impaired in Tgr rats (p < 0.01), and this impairment was more pronounced in males than females. Compromised bone strength in Tgr rats could not be accounted for by the reduction in mechanical load (body weight) and was not caused by impairment of the material properties of the calcified tissue (ultimate tensile stress), despite marked reductions in femoral mineral density (areal bone mineral density; p < 0.001). Microcomputerized tomographical analysis revealed significant modification of the architecture of trabecular bone in Tgr rats, with reductions in the number and thickness of trabeculae (p < 0.05) and in the degree of anisotropy (p < 0.01). The marked reduction in plasma insulin-like growth factor-1 in Tgr rats was accompanied by the development of high circulating leptin levels (p < 0.01). CONCLUSION: These results show that the changes in endocrinology and bone morphology associated with long-term moderate GHD in Tgr rats are accompanied by changes consistent with a significant reduction in the threshold for femoral fracture.

Effect of antisense knock-down of alpha(2a)- and alpha(2c)-adrenoceptors on the antinociceptive action of clonidine on trigeminal nociception in the rat.

Although activation of alpha(2)-adrenoceptors is known to play an important role in mediating antinociception, the contribution of various alpha(2)-adrenoceptor subtypes in modulating trigeminal nociception remains unknown since subtype specific agonists and antagonists are not available. The present study investigated the functional role of alpha(2)-adrenoceptor subtypes in modulating the N-methyl-D-aspartate-induced nociceptive behavior in the medullary dorsal horn by using antisense oligodeoxynucleotides to selectively knock-down the receptor subtypes. Microinjection of N-methyl-D-aspartate (2 nmol in 10 microl) through a cannula implanted dorsal to the medullary dorsal horn produced a total of 164.9+/-8.8 scratches in the facial region (n=14), and the scratching behavior lasted for 77.8+/-5.2s (n=14). Microinjection of clonidine, an alpha(2)-agonist (7 microg in 5 microl), 15 min prior to administration of N-methyl-D-aspartate, produced a reduction of 71.6% (n=12) in the number of scratches and a reduction of 57.5% (n=12) in the duration. The inhibitory effect of clonidine was blocked by idazoxan (n=4) and yohimbine (n=4), alpha(2) antagonists. In rats pretreated with the antisense probe to the alpha(2A) adrenoceptor, clonidine only produced a reduction of 7.3% in the number of scratches (n=12) and a reduction of 9% in the duration (n=12). The antinociceptive effect of clonidine recovered completely 4 days after termination of the alpha(2A) antisense oligodeoxynucleotide treatment. In contrast to the alpha(2A) antisense-treated animals, clonidine reduced the number of scratches and the duration by 85.5% (n=9) and 82.1% (n=9), respectively, in rats pretreated with the sense probe to the alpha(2A) adrenoceptor. The effect of clonidine was not altered in rats pretreated with the antisense or the sense probes to the alpha(2C) adrenoceptor. In the alpha(2C) antisense pretreated rats, clonidine reduced the number of scratches and the duration by 60.8% (n=11) and 44.5 % (n=11), respectively. In the sense-pretreated rats, clonidine produced a reduction of 69.1% in the number of scratches (n=9) and a reduction of 55.1% in the duration (n=9). In order to assess the effectiveness of the antisense treatment, the receptor expression was examined by immunohistochemistry. Antisense treatment reduced alpha(2A) and alpha(2C) receptor immunoreactivity in the medullary dorsal horn compared to the sense and the vehicle-treated animals. Quantitative image analysis revealed a significant decrease in pixel intensity following the antisense treatment. These results indicate that activation of alpha(2A) adrenoceptor plays an important role in mediating the antinociceptive effect of clonidine in the medullary dorsal horn in the rat.

The role of acute decompression and restoration of spinal alignment in the prevention of post-traumatic syringomyelia: case report and review of recent literature.

STUDY DESIGN: Case report. INTRODUCTION: Acute post-traumatic syringomyelia formation after spinal cord injury has been considered a rare complication. At this writing, most recent reports have surfaced in neurosurgical journals. As an entity, post-traumatic syringomyelia has not been widely appreciated. It has been confused with conditions such as Hansen's disease or ulnar nerve compression at the cubital tunnel. One study also demonstrated that the occurrence of syrinx is significantly correlated with spinal stenosis after treatment, and that an inadequate reduction of the spine may lead to the formation of syrinx. This reported case describes a patient in whom post-traumatic syringomyelia began to develop 3 weeks after injury, which improved neurologically after adequate decompression. SUMMARY OF BACKGROUND DATA: A 30-year-old man sustained a 20-foot fall at work. He presented with a complete spinal cord injury below T4 secondary to a T4 fracture dislocation. The patient underwent open reduction and internal fixation of T1-T8. After 3 weeks, the patient was noted to have ascending weakness in his bilateral upper extremities and some clawing of both hands. METHODS: A computed tomography myelogram demonstrated inability of contrast to pass through the T4-T5 region from a lumbar puncture. An incomplete reduction was noted. The canal showed significant stenosis. A magnetic resonance image of the patient's C-spine showed increased signal in the substance of the cord extending into the C1-C2 area. The patient returned to the operating room for T3-T5 decompressive laminectomy and posterolateral decompression including the pedicles, disc, and posterior aspect of the body. Intraoperative ultrasound monitoring showed a good flow of cerebrospinal fluid past the injured segment. RESULTS: On postoperative day 1, the clawing posture of the patient's hands was significantly diminished, and the patient noted an immediate improvement in his hand and arm strength. Over the next few days, the patient's strength in the bilateral upper extremities increased to motor Grade 4/5 on manual testing. A magnetic resonance image 4 weeks after decompression showed significant improvement in the cord diameter and signal. CONCLUSIONS: Post-traumatic syringomyelia has not been reported at so early a stage after injury. This disorder is an important clinical entity that must be recognized to prevent potentially fatal or devastating complications. As evidenced by the reported patient and the literature, if this disorder is discovered and treated early, permanent deficit can be avoided. The prevention of post-traumatic syringomyelia requires anatomic realignment and stabilization of the spine without stenosis, even in the case of complete injuries, to maintain the proper dynamics of cerebrospinal fluid flow.

Hyaluronic acid increases motility/intracellular CA2+ concentration in human sperm in vitro.

This study investigated the mechanisms of the stimulatory effect of hyaluronic acid on motility in human sperm in vitro. A method, involving the measurement of forward progression through an agarose gel. was used to measure sperm motility quantitatively. Changes in intracellular Ca2+ concentrations in sperm were detected using the fluorescent dye Fluo-3. The effects of hyaluronic acid (6.5, 65, 650 ng/mL) and nifedipine (32 nM) on sperm motility were investigated. The effects of hyaluronic acid, nifedipine (32 nM), A23187 (32 microM), and a monoclonal antibody to human CD44 (1 microg/mL) on changes in intracellular CA2+ concentrations were investigated. Hyaluronic acid significantly (p < .008) stimulated sperm motility and this was partially inhibited by nifedipine. A23187 significantly (p < .005) increased intracellular CA2+ concentrations. Hyaluronic acid significantly (p < .04) increased intracellular Ca2+ concentrations and this was inhibited by nifedipine and a monoclonal antibody to human CD44. Hyaluronic acid stimulated human sperm motility by increasing intracellular Ca2+ concentration, partially via an influx of extracellular Ca2+.

The role of ankle arthroscopy on the surgical management of ankle fractures.

Nineteen patients were prospectively randomized for operative treatment of their ankle fracture to be supplemented with or without ankle arthroscopy. All patients had an SER or PER fracture with an intact medial malleolus requiring operative treatment without evidence of intra-articular debris preoperatively. All patients underwent plate fixation of their fibula fracture and had a similar postoperative protocol. Ten patients were randomized to the control group with plate fixation only and nine patients randomized to the plate fixation plus operative arthroscopy. The average follow-up was 21 months. The arthroscopic examination of the study group revealed eight of the nine patients to have articular damage to the dome of the talus. Minimal arthroscopic treatment of these joints was required. All patients healed their fractures. No difference was noted between SF-36 scores or lower extremity scores between the two groups. At short-term follow-up, it does not appear that the arthroscopic procedure will impact upon the patient's eventual outcome in this small group of patients.

Prospective, randomized, double-blind study comparing single-agent antibiotic therapy, ciprofloxacin, to combination antibiotic therapy in open fracture wounds.

OBJECTIVE: The purpose of this study was to compare the efficacy of a single agent, ciprofloxacin, with that of combination antibiotic therapy consisting of cefamandole and gentamicin in all types of open fracture wounds. STUDY DESIGN: A prospective double-blind randomized clinical trial. SETTING: A Level 1 trauma center. PATIENTS: One hundred ninety-five consecutive patients with 203 open fractures were enrolled over a twenty-month period. Twenty-nine fractures from low-velocity gunshot wounds were excluded, and three other patients were excluded because of protocol violations. Our final number of patients were 163, with 171 open fractures. MAIN OUTCOME MEASUREMENT: The infection rates for Type I and Type II open fractures for both antibiotic groups were calculated. The infection rate of Type III open fractures for both antibiotic groups was also calculated. Chi-square analysis with Yates correction was used to assess statistical significance of two treatment groups. RESULTS: The infection rate for Types I and II open fractures in the ciprofloxacin group was 5.8 percent and 6 percent for the cefamandole/gentamicin group (p = 1.000). The infection rate for Type III open fractures for the ciprofloxacin group was 31 percent (8 of 26) versus 7.7 percent (2 of 26) for the cefamandole/gentamicin group (p = 0.079). There were no statistically significant differences in infection rate between the group treated with ciprofloxacin and that treated with cefamandole/gentamicin for Types I and II open fracture wounds. However, there appeared to be a high failure rate for the ciprofloxacin Type III open fracture group, with patients being 5.33 times more likely to become infected than those in the combination therapy group. Although this difference was not statistically significant, possibly because of the small sample size, there was a definite trend toward statistical significance. CONCLUSION: Single-agent antibiotic therapy with ciprofloxacin is effective in treatment of Type I and Type II open fracture wounds. However, on the basis of our results, we cannot recommend ciprofloxacin alone for Type III wounds. Possibly one can use fluoroquinolones in combination therapy, specifically as an alternate to an aminoglycoside.

Uveal lymphoid neoplasia: a clinical-pathologic correlation and review of the early form.

We report three cases of uveal lymphoid neoplasia that were diagnosed early in their course. One case exhibited a posterior form, presenting with progressive hyperopia from a serous-macular detachment and choroidal involvement along with retrobulbar involvement. This patient was treated with proton beam irradiation. Two cases displayed an anterior form, with fixed fleshy epibulbar masses resembling salmon patches, and choroidal involvement. The histologic findings from biopsy of these anterior masses are presented. One of these patients was treated with complete excision of the mass and double freeze-thaw cryotherapy of the scleral bed, and the other patient was treated with conventional photon beam irradiation. The clinical features of uveal lymphoid neoplasia in its early form are discussed. Evaluation and treatment strategies for these early forms of uveal lymphoid neoplasia are reviewed.

A quantitative immunofluorescence study of glomerular cell adhesion proteins in proteinuric states.

Whenever there is heavy proteinuria, the glomerular epithelial cells, the podocytes, show dramatic morphological changes which clearly demonstrate changes in cell adhesion. However, there is little information on the types of cell adhesion molecules expressed in the normal human glomerulus. Assessments of changes in cell adhesion molecules in human proteinuria have been confined to semi-quantitative immunostaining for integrins, and the results have not been entirely consistent. This study sought first to define which cell adhesion molecules are present in the normal glomerulus, using indirect immunofluorescence and a panel of antibodies directed against transmembrane adhesion proteins and against several cytoplasmic proteins which are known to be involved in adhesion. A wide variety of integrins were detected, the dominant form being alpha 3 beta 1. The cytoplasmic focal adhesion proteins vinculin, talin, paxillin, p130CAS, and pp125FAK were detected, although vinculin appeared to be confined mainly to the mesangium. The only intercellular adhesion molecule detected in the vicinity of the slit diaphragm was ZO-1; the results imply that the slit diaphragm does not bear a close relationship to any other form of intercellular junction. Changes in these adhesion components were also studied in proteinuria, using 18 cases each of minimal change nephropathy, 'early' membranous nephropathy, and normal controls. Fluorescence intensity was measured by image capture using a low light video camera and subsequent digital image analysis, an approach which demonstrated acceptable reproducibility. The most striking changes were an increase in phosphotyrosine and p130CAS in the nephrotic patients. Contrary to previous reports, little change was found in the expression of the most abundant integrins, nor did overall glomerular staining for ZO-1 alter. These results imply a controlled alteration in glomerular cell adhesion in nephrotic states in man, probable representing increased turnover of cell adhesion structures rather than the decrease which has been reported in short-term animal models. This is the first report of increased glomerular phosphotyrosine in man, which is associated with less stable adhesions and may be related to the loss of foot processes. Using human biopsy material, it was not possible to determine which proteins were phosphorylated, but the probable relationships to changes in cytoskeletal structure and slit diaphragm permeability justify further study.

European Gene Mapping Project (EUROGEM): breakpoint panels for human chromosomes based on the CEPH reference families. Centre d'Etude du Polymorphisme Humain.

Meiotic breakpoint panels for human chromosomes 2, 3, 4, 5, 6, 7, 8, 9, 10, 13, 14, 15, 17, 18, 20 and X were constructed from genotypes from the CEPH reference families. Each recombinant chromosome included has a breakpoint well-supported with reference to defined quantitative criteria. The panels were constructed at both a low-resolution, useful for a first-pass localization, and high-resolution, for a more precise placement. The availability of such panels will reduce the number of genotyping experiments necessary to order new polymorphisms with respect to existing genetic markers. This paper shows only a representative sample of the breakpoints detected. The complete data are available on the World Wide Web (URL http:/(/)www.icnet.uk/axp/hgr/eurogem++ +/HTML/data.html) or by anonymous ftp (ftp.gene.ucl.ac.uk in/pub/eurogem/maps/breakpoints).