A multi-lesional analysis of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: a single-centre analysis.

AIM: To conduct a multi-lesional computed tomography (CT) analysis of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) patients to determine volumetric changes in lesions over 5 years. MATERIALS AND METHODS: A retrospective case-note review was undertaken to identify 16 patients with histological and radiological features of DIPNECH between 2012-2021. Area and volume were calculated for 17 sets of lesions identified on high-resolution CT. Clinical data were extracted from electronic patient records, which included demographic data, outpatient clinic letters, histology reports, and imaging reports. RESULTS: One hundred and twenty-eight lesions were identified in 16 patients (one male, 15 female) and followed-up annually over a median 1,985 days (range 1,450-2,290). At year 1 follow-up, lesion area ranged from 1-48 mm2, and lesion volume ranged from 8-18,380 mm3; lesion area ranged from 1-45mm2 and lesion volume ranged from 11-17,800 mm3 and year 5. Half (8/16) of the patients had concomitant typical carcinoid tumours and one patient had an atypical carcinoid tumour. No statistically significant correlation (p<0.05) was found between lesion cross-sectional area or volume and duration of follow-up (years and days). No metastatic spread was observed at the time of analysis. CONCLUSIONS: No significant increase was observed in the size of over 100 lesions in patients with DIPNECH over a 5-year period and no metastasis occurred during the study period affirming the relatively indolent course of the disease.

Clinical features and outcomes of paediatric Spitz-type lesions.

INTRODUCTION AND OBJECTIVES: No definitive management guidelines exist for Spitz-type lesions; recommendations in the UK favour a 'safe' approach with a low threshold for excision. We aimed to describe Spitz-type lesions in children to further clarify the clinical features and outcomes. METHODS: We conducted a retrospective cohort study in Addenbrooke's Hospital, Cambridge, UK, and reviewed all patients aged ≤18 years with histologically confirmed Spitz-type lesions from November 2014 to September 2020. Information collected included patient demographics, lesion details, follow-up, outcomes and recurrence. RESULTS: Ninety-one children (male: female 42: 49; mean age at diagnosis: 9.4 years, SD: 4.6 years) were identified. Among them, 64 (70.3%) had classic Spitz or spitzoid naevi, 26 (28.6%) atypical Spitz tumours and 1 (1.1%) had spitzoid malignant melanoma based on histological features. On assessing the clinical features, where documented, we found that 22.0% (20/91) had amelanosis, 44.0% (40/91) had a raised bump, 12.1% (11/91) displayed bleeding, 25.0% (20/80) had non-uniform colour, 96.7% (88/91) were de novo lesions, 55.1% (43/78) were evolving in size and 35.9% (28/78) were evolving in colour. Fifty-nine patients (64.8%) were discharged without the need for follow-up, and the other 32 had a median follow-up time of 4 months. After confirmed excision, no incidences of local recurrence, distant metastases or mortality have been reported to date in all patients. CONCLUSIONS: The outcomes for paediatric Spitz-type lesions continue to be exceptionally good, remaining a low-risk lesion, which is more likely to be benign in children. Hence, we do not advocate aggressive management strategies for paediatric patients with clinically banal Spitz-type lesions.

Successful percutaneous coronary intervention in a patient with combined deficiency of FV and FVIII due to novel compound heterozygous mutations in LMAN1.

Percutaneous coronary intervention (PCI) in patients with congenital coagulation factor deficiencies presents a unique challenge. They are not only at increased risk of perioperative bleeding but can also suffer thrombosis of the stent as preventive anticoagulation and antiplatelet therapy is difficult. Several cases of successful PCI have been described in patients with haemophilia A and B, but there are no reports in patients with combined coagulation factor deficiencies. We used PCI to treat the coronary artery disease in a patient with the combined deficiency of factor V and factor VIII (F5F8D) and analysed the molecular basis of the disorder for this patient. A 68-year-old patient was admitted for urgent PCI with bare metal stent placement after the diagnosis of the F5F8D. Peripheral blood DNA was extracted for the sequence analysis of LMAN1 and MCFD2 genes. Mutations in LMAN1 was confirmed by molecular cloning of the PCR product and resequencing of the resulting clones. The patient underwent successful PCI with good long-term outcome. Our patient tolerated anticoagulation therapy well, with unfractionated heparin, and double antiplatelet therapy while he was initially supported with fresh frozen plasma and recombinant FVIII. Molecular analysis revealed that the patient carries unusual compound heterozygous frameshift mutations on the same microsatellite repeat region in exon 8 of LMAN1, one of which is a novel mutation (c.912delA). Our results suggest that patients with F5F8D can safely undergo PCI for coronary artery disease, with the treatment individualized to the specific patient.

Capillary versus venous haemoglobin determination in the assessment of healthy blood donors.

BACKGROUND AND OBJECTIVES: To determine the accuracy of fingerstick haemoglobin assessment in blood donors, the performance of a portable haemoglobinometer (HemoCue Hb 201+) was prospectively compared with that of an automated haematology analyzer (Cell-Dyn 4000). Haemoglobin values obtained by the latter were used as the 'true' result. MATERIAL AND METHODS: Capillary fingerstick samples were assayed by HemoCue in 150 donors. Fingerstick samples from two sites, one on each hand, were obtained from a subset of 50 subjects. Concurrent venous samples were tested using both HemoCue and Cell-Dyn devices. RESULTS: Capillary haemoglobin values (HemoCue) were significantly greater than venous haemoglobin values (HemoCue), which in turn were significantly greater than venous haemoglobin values by Cell-Dyn (mean ± SD: 14.05 ± 1.51, 13.89 ± 1.31, 13.62 ± 1.23, respectively; P < 0.01 for all comparisons among groups). Nine donors (6%) passed haemoglobin screening criteria (≥ 12.5 g/dl) by capillary HemoCue, but were deferred by Cell-Dyn values (false-pass). Five donors (3%) were deferred by capillary sampling, but passed by Cell-Dyn (false-fail). Substantial variability in repeated fingerstick HemoCue results was seen (mean haemoglobin 13.72 vs. 13.70 g/dl, absolute mean difference between paired samples 0.76 g/dl). Hand dominance was not a factor. CONCLUSIONS: Capillary samples assessed via a portable device yielded higher haemoglobin values than venous samples assessed on an automated analyzer. False-pass and false-fail rates were low and acceptable in the donor screening setting, with 'true' values not differing by a clinically significant degree from threshold values used to assess acceptability for blood donation.

Native pulmonary valve endocarditis requiring pulmonary valve replacement in adulthood: a case series.

Native pulmonary valve endocarditis is a rare phenomenon as native valve endocarditis tends to typically affect the left sided heart valves. However, the right-sided heart valves can be affected in patients with a history of intravenous drug use, whereby the tricuspid valve is most commonly affected. We present two cases who were diagnosed with native pulmonary valve endocarditis in the absence of congenital heart disease. In the first case, the native pulmonary valve endocarditis was probably a derivative of compounding factors of an enlarged underlying pulmonary artery and staphylococcal bacteraemia. In the second case, a common causal organism of native valve endocarditis following dental treatment and the resultant echocardiography findings was of significant interest. In summary, native pulmonary valve endocarditis is relatively rare complication in the adult population, especially in the absence of congenital heart disease.

A retrospective analysis of rates of allergic reaction to Patent V blue dye used in sentinel lymph node biopsies for melanoma.

Sentinel lymph node biopsies are a well-established component of the assessment and treatment pathway for patients with cutaneous melanoma in the UK. Commonly utilised techniques involve the use of blue dye which has an established risk of inducing allergic reactions in patients. Such reactions can be life-threatening, and this risk is important to highlight to patients. We conducted a retrospective review of all patients who had undergone this procedure at our melanoma centre in Cambridge, UK. From a group of 715 patients who received blue dye as part of the procedure, six patients suffered an allergic reaction (0.84%) with one of these treated as anaphylaxis. Our incidence of anaphylaxis is almost ten times greater than that reported in the NAP6 report led by the National Institute of Academic Anaesthesia and significantly higher than reported by others. We propose several reasons why our results differ from previous estimates. This study has focused only on patients undergoing a sentinel node procedure for melanoma, others have focused on such procedures performed on patients with breast cancer and some have combined the two. The administration technique, volume and anatomical distribution of disease all differ significantly from melanoma, possibly influencing rates and severity of allergic reactions.

Non-melanoma skin cancer activity during the COVID-19 pandemic- A single UK tertiary centre experience.

The pandemic caused by SARS-CoV-2 virus, also known as COVID-19, has generated shockwaves in medical and surgical practice. It has necessitated re-deployment of staff and resources to cater for the unpredictable increase in footfall and demand on healthcare systems. This study aimed to investigate how the restructuring of our service altered the triage and management of non-melanoma skin cancer (NMSC) during the pandemic's first wave rise and peak. We retrospectively analysed all patients who underwent a skin excision under local anaesthetic which revealed the presence of a basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) on histopathological analysis between 1st February 2020 - 31st May 2020 compared with the same period in 2019. There was a 158% increase in patients with excision of lesions confirmed on histopathological analysis as a NMSC during the COVID-19 period (168 vs. 65). In 2020, more excisions were performed by consultants (42.9% v 21.5%, p = 0.002) with a lower proportion of excisions with a close margin (27.7% v 17.8%, p = 0.096) and an involved margin (3.1% v 1.8%, p = 0.62). Five of these patients had their further management altered due to service constraints at this time The resource constraints secondary to the pandemic have yielded beneficial service adaptations with the incorporation of a more efficient model for the NMSC service. The sustainability of this model and its impact on training will require further examination when non-urgent and benign elective workload is slowly reinstated and plastic surgery trainees return to their original posts.

Lipid and mechano-gated 2P domain K(+) channels.

The two pore domain K(+) channels TREK and TRAAK are opened by membrane stretch. The activating mechanical force comes from the bilayer membrane and is independent of the cytoskeleton. Emerging work shows that mechano-gated TREK and TRAAK are opened by various lipids, including long chain polyunsaturated anionic fatty acids and neutral cone-shaped lysophospholipids. TREK-1 shares the properties of the Aplysia neuronal S channel, a presynaptic background K(+) channel involved in behavioral sensitization, a simple form of learning.

Off-pump external pericardial patch repair for post-infarct left ventricular free wall rupture: a case series.

We describe an off-pump surgical approach to this challenging condition supported by our results from a case series, which would add to existing literature in the management of this life-threatening complication. We identified seven patients who underwent surgical intervention for left ventricular (LV) free wall rupture at our institution. They were all diagnosed to have cardiac tamponade secondary to free wall rupture of the LV in the presence of acute myocardial infarction. The surgical technique comprised of utilizing an external pericardial patch which was secured using surgical biological glues (fibrin-based sealants or gelatin hydrogels). The 30-day mortality, 1-year survival and 2-year survival were 57, 42 and 42%, respectively. Advanced age, female gender and use of cardiopulmonary bypass were characteristics that were not significantly associated with survival. We advocate the use of an off-pump external pericardial patch repair strategy as a 'bridge to recovery' in this extremely high-risk group of patients.

A retrospective study of 694 Basal Cell Carcinoma excisions to quantify deep margin documentation and clearance compared to histological type and surgical margin.

AIMS: Basal cell carcinoma (BCC) is the most common malignancy worldwide. Although rarely a risk to life, they are potentially destructive and disfiguring. Current treatment guidelines are predominantly based on low-risk BCC and make no recommendations regarding the deep excision margin. We aim to clarify the prevalence of high-risk BCC and appropriate surgical management of the deep margin. METHODS: Data of 556 patients presenting for primary excision of 694 basal cell carcinoma to CUH Plastic Surgery between January 2017 and April 2018 were collected by capture of demographics, surgical notes and histology. We defined the deep surgical margin as numbered anatomical planes, with subcutaneous fat as 0, the first plane under this as 1 and so forth. This allowed comparison of the surgical excision depth, and resulting deep margin histology, across disparate sites. Histological margin clearance was analysed using ordinal regression of age, site, size, histological type and surgical margin. This allowed identification of factors associated with clear, close or incomplete lesion excision. Subgroup analysis was then performed to make recommendations for surgical margins to achieve adequate lesion clearance. RESULTS: Six hundred ninety-four BCCs were identified, 66% were male and the average age of patients was 74 years. Of the BCCs, 49% were nodular but 39% were mixed. An infiltrative component was seen in 24% (mixed infiltrative), but only 4% were purely infiltrative. Mean size, site and patient age were similar across histological types. Deep margin involvement was very rare in nodular or superficial BCCs but occurred in 7% of pure infiltrative and 5% of mixed infiltrative. Peripheral margins were very rarely involved in nodular BCCs but occurred in 9% of mixed infiltrative and 10% infiltrative despite similar surgical margins. A deep margin of the first underlying anatomical plane resulted uninvolved margins in 95% of infiltrative or mixed infiltrative BCC, but subcutaneous fat was sufficient for clearance in 95% of nodular, superficial and mixed non-infiltrative BCC. CONCLUSIONS: High-risk BCC was a common finding in our patient population. This was based not only on site and size but also on histological type. Infiltrative and mixed infiltrative BCCs have a higher risk of close or involved deep margins than other types. We recommend that they are excised to the first underlying anatomical plane. Nodular, superficial and mixed non-infiltrative BCC can usually be safely excised with a cuff of fat alone.

Inhalational anesthetics activate two-pore-domain background K+ channels.

Volatile anesthetics produce safe, reversible unconsciousness, amnesia and analgesia via hyperpolarization of mammalian neurons. In molluscan pacemaker neurons, they activate an inhibitory synaptic K+ current (IKAn), proposed to be important in general anesthesia. Here we show that TASK and TREK-1, two recently cloned mammalian two-P-domain K+ channels similar to IKAn in biophysical properties, are activated by volatile general anesthetics. Chloroform, diethyl ether, halothane and isoflurane activated TREK-1, whereas only halothane and isoflurane activated TASK. Carboxy (C)-terminal regions were critical for anesthetic activation in both channels. Thus both TREK-1 and TASK are possibly important target sites for these agents.

v-Abl activates c-myc transcription through the E2F site.

The v-abl oncogene of Abelson murine leukemia virus encodes a deregulated form of the cellular nonreceptor tyrosine kinase. v-Abl activates c-myc transcription, and c-Myc is an essential downstream component in the v-Abl transformation program. To explore the mechanism by which v-Abl activates c-myc transcription, a cotransfection assay was developed. We show that transactivation of a c-myc promoter by v-Abl requires the SH1 (tyrosine kinase) and SH2 domains of v-Abl; the C-terminal domains are not required for transactivation. The assay also identified the E2F site in the c-myc promoter as a v-Abl-responsive element. In addition, multimerized E2F sites were shown to be sufficient to confer v-Abl-dependent activation on a minimal promoter. This is the first identification of a v-Abl response element for transcriptional activation. v-Abl tyrosine kinase-dependent changes in proteins binding the c-myc E2F site were also demonstrated, including induction of a complex containing DP1, p107, cyclin A, and cdk2. Identification of v-Abl-dependent changes in E2F-binding proteins provides an important link between v-Abl, transcription, cell cycle regulation, and control of cellular growth.

Properties and modulation of mammalian 2P domain K+ channels.

Mammalian 2P domain K(+) channels are responsible for background or 'leak' K(+) currents. These channels are regulated by various physical and chemical stimuli, including membrane stretch, temperature, acidosis, lipids and inhalational anaesthetics. Furthermore, channel activity is tightly controlled by membrane receptor stimulation and second messenger phosphorylation pathways. Several members of this novel family of K(+) channels are highly expressed in the central and peripheral nervous systems in which they are proposed to play an important physiological role. The pharmacological modulation of this novel class of ion channels could be of interest for both general anaesthesia and ischaemic neuroprotection.

Rectal and bladder dose reduction with the addition of intravaginal balloons to vaginal packing in intracavitary brachytherapy for cervical cancer.

PURPOSE: The use of intravaginal Foley balloons in addition to conventional packing during high-dose-rate (HDR) tandem and ovoids intracavitary brachytherapy (ICBT) is a means to improve displacement of organs at risk, thus reducing dose-dependent complications. The goal of this project was to determine the reduction in dose achieved to the bladder and rectum with intravaginal Foley balloons with CT-based planning and to share our packing technique. METHODS AND MATERIALS: One hundred and six HDR-ICBT procedures performed for 38 patients were analyzed for this report. An uninflated Foley balloon was inserted into the vagina above and below the tandem flange separately and secured in place with vaginal packing. CT images were then obtained with both inflated and deflated Foley balloons. Plan optimization occurred and dose volume histogram data were generated for the bladder and rectum. Maximum dose to 0.1, 1.0, and 2.0 cm(3) volumes for the rectum and bladder were analyzed and compared between inflated and deflated balloons using parametric statistical analysis. RESULTS: Inflation of intravaginal balloons allowed significant reduction of dose to the bladder and rectum. Amount of reduction was dependent on the anatomy of the patient and the placement of the balloons. Displacement of the organs at risk by the balloons allowed an average of 7.2% reduction in dose to the bladder (D0.1 cm(3)) and 9.3% to the rectum (D0.1 cm(3)) with a maximum reduction of 41% and 43%, respectively. CONCLUSIONS: For patients undergoing HDR-ICBT, a significant dose reduction to the bladder and rectum could be achieved with further displacement of these structures using intravaginal Foley balloons in addition to conventional vaginal packing.

Factors that affect the expression of beta-amyloid precursor protein immunoreactivity in the rat retina.

Expression of beta-amyloid precursor protein immunoreactivity in the rat retina was studied after intravitreal injection of substances known to influence neural function in different ways. The substances were the excitatory amino acid glutamate, the inflammatory agent lipopolysaccharide, the depolarizing agent potassium chloride, and the potassium channel blocker barium chloride. In comparison with controls, more beta-amyloid precursor protein immunoreactivity was observed in the radial process of Müller glial cells 24 hours after injection of glutamate or lipopolysaccharide. In contrast, administration of barium chloride greatly reduced immunostaining in Müller cells. Further, an increase in immunostaining was observed in the inner and outer plexiform layers in retinas treated with any of the 3 chemicals, and in blood vessels after injection of glutamate and lipopolysaccharide. These observations suggest that multiple but specific signaling pathways are involved in regulating expression of beta-amyloid precursor protein in distinct cell types and regions in the retina.

Effects of undernutrition on gliogenesis and glial maturation in rat corpus callosum.

Rats were undernourished by halving the mother's food intake from the sixth day of pregnancy onwards and through lactation. At weaning, the young rats were restricted to half the normal weight of food. A combination of light and electron microscopic techniques was used to study the effects of this regime on gliogenesis and glial maturation in the corpus callosum of animals aged between 15 and 48 days. A disturbance of neuroglial proliferation was suggested by the finding of an increased proportion of astroglia relative to oligodendroglia in the 15-day-old undernourished rats, indicating a delay in the acquisition of cells produced relatively late in development. Impaired differentiation of oligodendroglia was suggested by the finding in treated animals of increased light oligodendrocytes at 15 days and a deficit of dark oligodendrocytes at 48 days, relative to controls. The previously observed retardation in myelin acquisition seems thus to be related to a delay in the differentiation of oligodendroglia, although it seems likely that the proliferation of these cells is also disturbed in undernutrition.

Distribution of septohippocampal neurons containing parvalbumin or choline acetyltransferase in the rat brain.

A combination of retrograde transport of horseradish peroxidase or wheat germ agglutinin-colloidal gold with either single or double-label immunohistochemistry is used to describe the comparative topographic distribution of parvalbumin- and choline acetyltransferase-immunoreactive septal neurons that project to the hippocampal formation of the rat. The morphometric parameters of the retrogradely labelled, parvalbumin-containing neurons were very similar, if not identical, to those neurons of the midline and medial part of the medial septum and the diagonal band regions that had previously been shown to be immunoreactive for gamma-aminobutyric acid or for glutamate decarboxylase following colchicine treatment. The total number of parvalbumin-immunoreactive and choline acetyltransferase-positive retrogradely labelled cells was counted at 9 representative levels through the rostrocaudal extension (from 2.4 mm anterior to the level of bregma) of the medial septal-diagonal band complex. In the whole medial septum-vertical limb of the diagonal band region, about 33% of the total retrogradely labelled neurons showed immunoreactivity to parvalbumin, whereas the parvalbumin-negative cells were mainly choline acetyltransferase-immunopositive. In comparison with the average figure, the proportion of the retrogradely labelled parvalbumin-containing neurons was higher in the middle part (around 1.5 mm anterior to the bregma) than in either the rostral or caudal ends. The reverse was true for the distribution of the cholinergic septohippocampal neurons. At the maximum levels the parvalbumin-immunoreactive neurons accounted for more than half of the total retrogradely labelled cells in 4 out of 6 rats. Moreover, within the complexity of the septal neurons, a marked regularity of topographic organisation was observed in the distribution of retrogradely labelled parvalbumin-containing GABAergic and choline acetyltransferase-positive cholinergic neurons as if they were subdivided cytoarchitectonically.

A low-affinity nerve growth factor receptor antibody is internalized and retrogradely transported selectively into cholinergic neurons of the rat basal forebrain.

The mechanism by which nerve growth factor transduces its signal in responsive cells is yet to be clearly defined. However, it has been suggested that the internalization of nerve growth factor, the first step in the retrograde flow of nerve growth factor, is a property of the high-affinity receptors, p140trkA. Here we show that when a monoclonal antibody (MC 192), which immunoprecipitates p75NGFR (the low-affinity 75,000 mol. wt nerve growth factor receptor protein) and not p140trkA, was administered into the dorsal hippocampal formation of the rats, it was internalized and retrogradely transported to the cell bodies residing in the medial septum-diagonal band complex. The topographic organization and the localization of these neurons containing retrogradely transported p75NGFR antibody were strikingly similar to those nerve cells immunostained for choline acetyltransferase in the immediately-adjacent section, indicating that the neurons which contained p75NGFR antibody were cholinergic neurons. A double-label immunocytochemistry confirmed this conclusion. On the other hand, none of the parvalbumin-positive GABAergic neurons contained retrogradely transported p75NGFR antibody. Moreover, in contrast to specific transport of p75NGFR antibody into cholinergic neurons, when wheat germ agglutinin-colloidal gold was injected into the hippocampus at the same levels, it was taken up and retrogradely transported into both choline acetyltransferase-positive cholinergic and parvalbumin-immunoreactive GABAergic neurons in the medial septum-diagonal band complex.

Immunohistochemical localization of cells containing nerve growth factor receptors in the different regions of the adult rat forebrain.

Conditions have been optimized for an immunohistochemical procedure for the localization of nerve growth factor receptor-containing cells in the brain. Using this immunohistochemical procedure, the normal morphology and distribution of the nerve growth factor receptor-containing neurons of the adult rat forebrain have been studied, and the findings compared with observations on the choline acetyltransferase-positive neurons present either in the immediately-adjacent sections or in the medially-divided half of the same section. Unlike in the peripheral nervous system, only neurons showed immunoreactivity to the nerve growth factor receptor in the brain. Both the nerve growth factor receptor- and choline acetyltransferase-immunoreactive cells appear to form a continuous anteroposterior band, which includes the olfactory tubercle, the medial septal nucleus, the vertical and horizontal limbs of the diagonal band and the basal nucleus. In each subdivision of the basal forebrain, the topographic organization, the localization, the intensity of the immunoreaction and the total cell number of nerve growth factor receptor- and of choline acetyltransferase-immunoreactive neurons were strikingly similar, indicating that nearly all nerve growth factor receptor-containing cells were cholinergic neurons. However, in the striatum, only about half the number of the choline acetyltransferase-positive cells showed immunopositive reactions to the nerve growth factor receptor, and, also, in the nerve growth factor receptor-containing neurons the intensity of the reaction product was much less than the choline acetyltransferase immunoreactivity. In the neurons of the basal forebrain nuclei, the choline acetyltransferase immunoreaction product was uniformly distributed on the cell bodies, while the nerve growth factor receptor immunoreaction product was present also as intensely stained granules on the cell somata and the dendrites. The mean diameter and the mean cross-sectional area of the nerve growth factor receptor-containing neurons were least in the medial septal nucleus and were greatest in the basal nucleus, and showed a gradation in cell size going from the medial septal nucleus through the nucleus of the diagonal band and extending more posteriorly to the basal nucleus.

Thyroid hormone and development of the rat hippocampus: cell acquisition in the dentate gyrus.

A quantitative autoradiographic histological study was carried out to examine mechanisms underlying the reduction in the rates of growth and of cell acquisition, including that of granule cells, in the dentate gyrus of hypothyroid rats. Thyroid deficiency in early life had no effect on the replication of intrinsic cells present in the polymorph and granular layers. The pyknotic index was also normal in the "proliferative zone", polymorph layer and granule cell layer, indicating that thyroid hormone had no effect on the survival of replicating, migrating or maturing granule cells. By contrast, the arrival of migrating cells from the "proliferative zone" to the granular layer was severely retarded in thyroid deficiency. This deficit was rapidly restored after a physiological dose of thyroxine given to hypothyroid rats. The present findings are consistent with our previous proposal that the role of thyroid hormone in the formation and/or the maintenance of nerve cells is related to changes in either cell migration or maturation, rather than to alterations in the replication of germinal cells.