bluuebunny/crossref_metadata_2025 huggingface dataset:
The block to membrane fusion differs with the site of ligand insertion in modified retroviral envelope proteins
Authors: Ryu Byoung Y. , Zavorotinskaya Tatiana , Trentin Bernadette , Albritton Lorraine M.
Published: March 2008

Efforts to achieve cell type-specific transduction of retroviral vectors for gene therapy have centred on modification of the envelope protein (Env). Typically, addition of a ligand to Env gives binding to the new or target receptor, but little or no infection, and affects the subunit association of the modified Env. We previously discovered two point mutations that increase targeted infection by over 1000-fold when added to an Env modified by N-terminal insertion of the receptor-binding domain from amphotropic murine leukemia virus Env. Here, we asked whether these mutations would similarly increase transduction by Env modified with a clinically relevant ligand, human interleukin-13 (IL-13L). Addition of the point mutations stabilized the weak subunit association observed in some IL-13L-modified Env proteins, but infection via the target IL-13 receptor still did not occur. Fluorescence-based cell–cell fusion assays and studies with a membrane-curving agent revealed that defects in membrane fusion differed with the site of ligand insertion. When IL-13 was inserted into the N terminus of Env, membrane fusion was blocked prior to membrane-lipid mixing, regardless of whether flanking flexible linkers were added. Unexpectedly, insertion of IL-13 in the proline-rich region showed evidence of initiation of fusion and fusion-peptide exposure, but fusion was blocked at a subsequent step prior to fusion-pore formation. Thus, the site of ligand insertion influenced initiation of membrane fusion and its progression. These observations suggest that a novel site for ligand insertion must be identified before clinically useful targeted transduction will be achieved.
Mutagenesis of the West Nile virus NS2B cofactor domain reveals two regions essential for protease activity
Authors: Chappell Keith J. , Stoermer Martin J. , Fairlie David P. , Young Paul R.
Published: March 2008

The flavivirus NS2B/NS3 protease has received considerable attention as a target for the development of antiviral compounds. While substrate based inhibitors have been the primary focus to date, an approach focussing on NS2B cofactor displacement could prove to be an effective alternative. To understand better the role of the NS2B cofactor in protease activation, we conducted an alanine mutagenesis screen throughout the 42-residue central cofactor domain (NS2B51–92) of West Nile virus (WNV). Two sites critical for proteolytic activity were identified (NS2B59–62 and NS2B75–87), where the majority of substitutions were found to significantly decrease proteolytic activity of a recombinant WNV NS2B/NS3 protease. These findings provide mechanistic insights into the structural and functional role that the cofactor may play in the substrate-bound and free protease complexes as well as providing novel sites for targeting new antiviral inhibitors.
Association of the transcriptional response of soybean plants with soybean mosaic virus systemic infection
Authors: Babu Mohan , Gagarinova Alla G. , Brandle James E. , Wang Aiming
Published: March 2008

Compatible virus infection induces and suppresses host gene expression at the global level. These gene-expression changes are the molecular basis of symptom development and general stress and defence-like responses of the host. To assess transcriptional changes in soybean plants infected with soybean mosaic virus (SMV), the first soybean trifoliate leaf, immediately above the SMV-inoculated unifoliate leaf, was sampled at 7, 14 and 21 days post-inoculation (p.i.) and subjected to microarray analysis. The identified changes in gene expression in soybean leaves with SMV infection at different time points were associated with the observed symptom development. By using stringent selection criteria (≥2- or ≤−2-fold change and aQvalue of ≤0.05), 273 (1.5 %) and 173 (0.9 %) transcripts were identified to be up- and downregulated, respectively, from 18 613 soybean cDNAs on the array. The expression levels of many transcripts encoding proteins for hormone metabolism, cell-wall biogenesis, chloroplast functions and photosynthesis were repressed at 14 days p.i. and were associated with the highest levels of viral RNA in the host cells. A number of transcripts corresponding to genes involved in defence were either downregulated or not affected at the early stages of infection, but upregulated at the late stages, indicating that the plant immune response is not activated until the late time points of infection. Such a delayed defence response may be critical for SMV to establish its systemic infection.
Essential role of PKCδ in histone deacetylase inhibitor-induced Epstein–Barr virus reactivation in nasopharyngeal carcinoma cells
Authors: Lee Heng-Huan , Chang Shih-Shin , Lin Sue-Jane , Chua Huey-Huey , Tsai Tze-Jiun , Tsai Kevin , Lo You-Chang , Chen Hong-Chen , Tsai Ching-Hwa
Published: March 2008

Histone deactylase inhibitors (HDACi) are common chemotherapeutic agents that stimulate Epstein–Barr virus (EBV) reactivation; the detailed mechanism remains obscure. In this study, it is demonstrated that PKCδ is required for induction of the EBV lytic cycle by HDACi. Inhibition of PKCδ abrogates HDACi-mediated transcriptional activation of the Zta promoter and downstream lytic gene expression. Nuclear translocation of PKCδ is observed following HDACi stimulation and its overexpression leads to progression of the EBV lytic cycle. Our study suggests that PKCδ is a crucial mediator of EBV reactivation and provides a novel insight to study the regulation of the EBV lytic cycle.
Specificity and functional interaction of the polymerase complex proteins of human and avian metapneumoviruses
Authors: de Graaf Miranda , Herfst Sander , Schrauwen Eefje J. A. , Choi Ying , van den Hoogen Bernadette G. , Osterhaus Albert D. M. E. , Fouchier Ron A. M.
Published: March 2008

Human metapneumovirus (HMPV) and avian metapneumovirus (AMPV) have a similar genome organization and protein composition, but a different host range. AMPV subgroup C (AMPV-C) is more closely related to HMPV than other AMPVs. To investigate the specificity and functional interaction of the polymerase complex proteins of human and avian metapneumoviruses, a minireplicon system was generated for AMPV-C and used in combination with minireplicon systems for HMPV lineages A1 and B1. Viral RNA-like molecules representing HMPV-A1 and -B1, AMPV-A and -C and human respiratory syncytial virus were replicated efficiently by polymerase complexes of HMPV-A1 and -B1 and AMPV-C, but not by polymerase complexes of bovine parainfluenza virus 3. Upon exchange of HMPV and AMPV-C polymerase complex components, all chimeric polymerase complexes were functional; exchange between HMPVs did not result in altered polymerase activity, whereas exchange between HMPVs and AMPV-C did. Recombinant HMPV-B1 viruses in which polymerase genes were exchanged with those of HMPV-A1 replicated with normal kinetics in vitro, whilst replacement with AMPV-C genes resulted in moderate differences in virus replication. In hamsters, recombinant HMPV-B1 viruses in which individual polymerase genes were exchanged with those of AMPV-C were attenuated, irrespective of the results obtained with minireplicon systems or in vitro replication assays. This study provides insight into the specificity and functional interaction of polymerase complex proteins of human and avian metapneumoviruses, but neither minireplicon systems nor in vitro replication kinetics were found to be predictive for attenuation in permissive animals.
Rapid evolutionary dynamics of zucchini yellow mosaic virus
Authors: Simmons Heather E. , Holmes Edward C. , Stephenson Andrew G.
Published: March 2008

Zucchini yellow mosaic virus (ZYMV) is an economically important virus of cucurbit crops. However, little is known about the rate at which this virus has evolved within members of the familyCucurbitaceae, or the timescale of its epidemiological history. Herein, we present the first analysis of the evolutionary dynamics of ZYMV. Using a Bayesian coalescent approach we show that the coat protein of ZYMV has evolved at a mean rate of 5.0×10−4nucleotide substitutions per site, per year. Notably, this rate is equivalent to those observed in animal RNA viruses. Using the same approach we show that the lineages of ZYMV sampled here have an ancestry that dates back no more than 800 years, suggesting that human activities have played a central role in the dispersal of ZYMV. Finally, an analysis of phylogeographical structure provides strong evidence for thein situevolution of ZYMV within individual countries.
Effect of phosphorylation on the transactivation activity of Epstein–Barr virus BMRF1, a major target of the viral BGLF4 kinase
Authors: Yang Pei-Wen , Chang Shih-Shin , Tsai Ching-Hwa , Chao Yi-Hsin , Chen Mei-Ru
Published: March 2008

Modification of human herpesvirus DNA polymerase processivity factors (PFs) by phosphorylation occurs frequently during viral lytic replication. However, functional regulation of the herpesvirus PFs through phosphorylation is not well understood. In addition to processivity, the PF BMRF1 of Epstein–Barr virus can function as a transactivator to activate the BHLF1 promoter within the lytic origin of replication (oriLyt), which is assumed to facilitate DNA replication through remodelling viral chromatin structure. BMRF1 is known to be phosphorylated by the viral BGLF4 kinase, but its impact on BMRF1 function is unclear. Seven candidate BGLF4 target sites were predicted within a proline-rich region between the DNA-processivity and nuclear-localization domains of BMRF1. We show that four of these residues, Ser-337, Thr-344, Ser-349 and Thr-355, are responsible for the BGLF4-induced hyperphosphorylation of BMRF1. In functional analyses, a phosphorylation-mimicking mutant of BMRF1 shows similar nuclear localization, as well as DNA-binding ability, to the wild type; however, it displays stronger synergistic activation of the BHLF1 promoter with Zta. Notably, BGLF4 downregulates BMRF1 transactivation and enhances the transactivation activity of Zta and the synergistic activation of BMRF1 and Zta on the BHLF1 promoter. Our findings suggest that BGLF4 may modulate the activation of the oriLyt BHLF1 promoter coordinately through multiple mechanisms to facilitate optimal oriLyt-dependent viral DNA replication.
A viral histone H4 encoded by Cotesia plutellae bracovirus inhibits haemocyte-spreading behaviour of the diamondback moth, Plutella xylostella
Authors: Gad Wael , Kim Yonggyun
Published: March 2008

Histone H4 is highly conserved and forms a central-core nucleosome with H3 in eukaryotic chromatin. Its covalent modification at the protruding N-terminal region from the nucleosomal core can change the chromatin conformation in order to regulate gene expression. A viral H4 was found in the genome of Cotesia plutellae bracovirus (CpBV). The obligate host of the virus is an endoparasitoid wasp, C. plutellae, which parasitizes the diamondback moth, Plutella xylostella, and interrupts host development and immune reactions. CpBV has been regarded as a major source for interrupting the physiological processes during parasitization. CpBV H4 shows high sequence identity with the amino acid sequence of P. xylostella H4 except for an extended N-terminal region (38 aa). This extended N-terminal CpBV H4 contains nine lysine residues. CpBV H4 was expressed in P. xylostella parasitized by C. plutellae. Western blot analysis using a wide-spectrum H4 antibody showed two H4s in parasitized P. xylostella. In parasitized haemocytes, CpBV H4 was detected predominantly in the nucleus and was highly acetylated. The effect of CpBV H4 on haemocytes was analysed by transient expression using a eukaryotic expression vector, which was injected into non-parasitized P. xylostella. Expression of CpBV H4 was confirmed in the transfected P. xylostella by RT-PCR and immunofluorescence assays. Haemocytes of the transfected larvae lost their spreading ability on an extracellular matrix. Inhibition of the cellular immune response by transient expression was reversed by RNA interference using dsRNA of CpBV H4. These results suggest that CpBV H4 plays a critical role in suppressing host immune responses during parasitization.
Multiple waves of recent DNA transposon activity in the bat, Myotis lucifugus
Authors: Ray David A. , Feschotte Cedric , Pagan Heidi J.T. , Smith Jeremy D. , Pritham Ellen J. , Arensburger Peter , Atkinson Peter W. , Craig Nancy L.
Published: March 2008

DNA transposons, or class 2 transposable elements, have successfully propagated in a wide variety of genomes. However, it is widely believed that DNA transposon activity has ceased in mammalian genomes for at least the last 40 million years. We recently reported evidence for the relatively recent activity of hAT and Helitron elements, two distinct groups of DNA transposons, in the lineage of the vespertilionid bat Myotis lucifugus. Here, we describe seven additional families that have also been recently active in the bat lineage. Early vespertilionid genome evolution was dominated by the activity of Helitrons, mariner-like and Tc2-like elements. This was followed by the colonization of Tc1-like elements, and by a more recent explosion of hAT-like elements. Finally, and most recently, piggyBac-like elements have amplified within the Myotis genome and our results indicate that one of these families is probably still expanding in natural populations. Together, these data suggest that there has been tremendous recent activity of various DNA transposons in the bat lineage that far exceeds those previously reported for any mammalian lineage. The diverse and recent populations of DNA transposons in genus Myotis will provide an unprecedented opportunity to study the impact of this class of elements on mammalian genome evolution and to better understand what makes some species more susceptible to invasion by genomic parasites than others.
Quantitative evidence for conserved longevity pathways between divergent eukaryotic species
Authors: Smith Erica D. , Tsuchiya Mitsuhiro , Fox Lindsay A. , Dang Nick , Hu Di , Kerr Emily O. , Johnston Elijah D. , Tchao Bie N. , Pak Diana N. , Welton K. Linnea , Promislow Daniel E.L. , Thomas James H. , Kaeberlein Matt , Kennedy Brian K.
Published: March 2008

Studies in invertebrate model organisms have been a driving force in aging research, leading to the identification of many genes that influence life span. Few of these genes have been examined in the context of mammalian aging, however, and it remains an open question as to whether and to what extent the pathways that modulate longevity are conserved across different eukaryotic species. Using a comparative functional genomics approach, we have performed the first quantitative analysis of the degree to which longevity genes are conserved between two highly divergent eukaryotic species, the yeast Saccharomyces cerevisiae and the nematode Caenorhabditis elegans. Here, we report the replicative life span phenotypes for single-gene deletions of the yeast orthologs of worm aging genes. We find that 15% of these yeast deletions are long-lived. In contrast, only 3.4% of a random set of deletion mutants are long-lived—a statistically significant difference. These data suggest that genes that modulate aging have been conserved not only in sequence, but also in function, over a billion years of evolution. Among the longevity determining ortholog pairs, we note a substantial enrichment for genes involved in an evolutionarily conserved pathway linking nutrient sensing and protein translation. In addition, we have identified several conserved aging genes that may represent novel longevity pathways. Together, these findings indicate that the genetic component of life span determination is significantly conserved between divergent eukaryotic species, and suggest pathways that are likely to play a similar role in mammalian aging.
ALLPATHS: De novo assembly of whole-genome shotgun microreads
Authors: Butler Jonathan , MacCallum Iain , Kleber Michael , Shlyakhter Ilya A. , Belmonte Matthew K. , Lander Eric S. , Nusbaum Chad , Jaffe David B.
Published: March 2008

New DNA sequencing technologies deliver data at dramatically lower costs but demand new analytical methods to take full advantage of the very short reads that they produce. We provide an initial, theoretical solution to the challenge of de novo assembly from whole-genome shotgun “microreads.” For 11 genomes of sizes up to 39 Mb, we generated high-quality assemblies from 80× coverage by paired 30-base simulated reads modeled after real Illumina-Solexa reads. The bacterial genomes of Campylobacter jejuni and Escherichia coli assemble optimally, yielding single perfect contigs, and larger genomes yield assemblies that are highly connected and accurate. Assemblies are presented in a graph form that retains intrinsic ambiguities such as those arising from polymorphism, thereby providing information that has been absent from previous genome assemblies. For both C. jejuni and E. coli, this assembly graph is a single edge encompassing the entire genome. Larger genomes produce more complicated graphs, but the vast majority of the bases in their assemblies are present in long edges that are nearly always perfect. We describe a general method for genome assembly that can be applied to all types of DNA sequence data, not only short read data, but also conventional sequence reads.
Pattern of skin and nail changes in chronic renal failure in Nepal: A hospital‐based study
Authors: AMATYA Beni , AGRAWAL Sudha , DHALI Tapan , SHARMA Sanjib , PANDEY Shyam Sunder
Published: March 2008

Chronic renal failure, regardless of its cause, often produces specific dermatological abnormalities, which can develop long before failure manifests clinically. Our aim was to study the clinical pattern of skin and nail changes in chronic renal failure and also study the associations of these changes with age, sex, etiology and duration of the chronic renal failure. A total of 104 diagnosed cases of chronic renal failure were included in the study over a period of 1 year. Equal numbers of age‐ and sex‐matched individuals were taken as controls. The male : female ratio was 1.4:1. The mean duration of chronic renal failure was 19 ± 20 months. Among cases and controls, 72% and 16% had skin changes, respectively. Xerosis was the most common of the skin changes (28%), followed by hyperpigmentation (20%), pruritus (15%), infectious diseases (5%) and other skin changes (33%) in chronic renal failure patients. Abnormal nail changes were seen in 82% of the cases compared to only 8% of the controls. In the cases, white nail was most common followed by brown and half‐and‐half nail. Pruritus was significantly higher in the dialysis group whereas the nail changes were significantly higher in the non‐dialysis group. The skin and nail changes were common in chronic renal failure and manifested in various forms. Thus, thorough inspection of the integument might reveal markers of occult renal disease.
NON‐AUTONOMY OF HORMONE SECRETION IN PRIMARY HYPERPARATHYROIDISM
Authors: MURRAY T. M. , PEACOCK M. , POWELL D. , MONCHIK J. M. , POTTS J. T.
Published: March 2008

Parathyroid hormone (PTH) was measured by radioimmunoassay in the plasma of twenty patients with surgically proven primary hyperparathyroidism during intravenous infusions of calcium and/or EDTA. All patients studied showed significant increases in plasma PTH during induced hypocalcaemia and significant decreases in plasma PTH during induced hypercalcaemia. The secretion of para thyroid hormone was not autonomous in these patients with primary hyperparathyroidism, regardless of histological type, but varied with induced changes in serum calcium concentration. The presence of immunoreactive hormonal sub‐fragments in plasma seems the most likely explanation for the sharp contrast between our data and earlier studies. In spite of the difficulties presented by this complex pattern of hormonal metabolism, the radioimmunoassay for parathyroid hormone is clinically quite useful, particularly in the differential diagnosis of hypercalcaemia.
THE ROLE OF TRIIODOTHYRONINE (T3) IN THE MAINTENANCE OF EUTHYROIDISM IN ENDEMIC GOITRE
Authors: PHARAOH P. O. D. , LAWTON N. F. , ELLIS S. M. , WILLIAMS E. S. , EKINS R. P.
Published: March 2008

Serum concentrations of triiodothyronine (T3), thyroxine (T4) and thyroid stimulating hormone (TSH) have been measured in subjects from an endemic goitrous area of New Guinea. An increase in TSH concentration and a decrease in T4 concentration was found in both goitrous and non‐goitrous subjects, both abnormalities being more frequent in the goitrous group. In the majority of subjects (93%) the T3 level fell within the normal range. Euthyroidism appears to be preserved in the iodine deficient state by the continued production of normal amounts of T3, the intrinsic metabolic activity of T4 being relatively unimportant.
AN ASSESSMENT OF THE METYRAPONE TEST
Authors: SHAHMANESH M. , HARTOG M. , CROOK D.
Published: March 2008

The degree of 11β‐hydroxylase inhibition produced during a 24 hr metyrapone test was assessed in sixteen normal subjects and seven patients with Cushing's syndrome using a urinary GLC method which distinguishes between 11‐deoxy‐corticosteroids and 11‐oxygenated corticosteroids. A doubling over basal values and a rise of total urinary corticosteroids of more than 10 mg in 24 hr was seen in all the fifteen normal subjects who achieved over 70% enzyme inhibition in at least one 24 hr period after the administration of metyrapone.

All patients with Cushing's syndrome showed over 70% enzyme inhibition. On the basis of the test it was possible to distinguish between pituitary dependent Cushing's syndrome and that caused by an adrenal adenoma. A single patient with the ectopic ACTH syndrome showed a normal metyrapone response.

The urinary GLC method provides a simple means of assessing the adequacy of enzyme inhibition produced by metyrapone.
SERUM TSH RESPONSES TO INTRAVENOUSLY AND ORALLY ADMINISTERED TRH IN MAN AFTER THYROIDECTOMY FOR CARCINOMA OF THE THYROID
Authors: FAIRCLOUGH P. D. , CRYER R. J. , McALLISTER J. , HAWKINS L. , JONES A. E. , McKENDRICK M. , HALL R. , BESSER G. M.
Published: March 2008

Fourteen patients whose thyroid glands had been ablated for carcinoma were given intravenous or oral thyrotrophin releasing hormone (TRH) at intervals after stopping replacement thyroid hormone. Despite continuing the TRH infusion, serum thyrotrophin (TSH) rose to reach a peak at 120 min after the start of the infusion, and then fell again towards the pre‐treatment values. Significant responses were seen by 4 days after stopping triodothyronine (T3), but progressively increased with longer intervals off T3. Oral TRH gave a similar pattern of responses. Patients maintained on thyroxine (T4) and changed to T3 4 weeks prior to treatment had smaller TSH responses to TRH than patients maintained continuously on T3. It would seem that: (1) TRH promotes TSH release faster than it promotes synthesis of new hormone under the conditions studied, and (2) that long‐term administration of T3 suppresses TSH secretion from the pituitary in response to TRH less than thyroxine. While it is possible to elevate the serum TSH levels of these patients with thyroid carcinoma into the rane normally seen in primary hypothyroidism by the use of TRH prior to administration of radioiodine without production of clinical symptoms of hypothyroidism, we do not yet know whether such elevation is of benefit in treatment.
OSTEOID MINERALIZATION DEFECT IN PRIMARY HYPERPARATHYROIDISM
Authors: BORDIER J. , WOODHOUSE N. J. Y. , SIGURDSSON G. , JOPLIN G. F.
Published: March 2008

Using a quantitative histological technique, four unselected patients with primary hyperparathyroidism were investigated and all were found to have a delayed or defective mineralization of osteoid, although their diet contained an adequate amount of vitamin D. This abnormality was most marked in the one patient with radiological bone disease. Mineralization of osteoid occurred during subsequent vitamin D administration, together with an improvement in 45Ca absorption by the gut; osteoclast numbers and serum acid phosphatase levels also increased.

We suggest that (1) endogenous vitamin D deficiency and hyperparathyroidism frequently co‐exist, (2) vitamin D metabolism is abnormal in hyperparathyroidism, and (3) radiological loss of bone density and erosions in hyperparathyroidism are due to impairment of the process of bone repair, i.e. there is defective mineralization of the osteoid which is laid down by osteoblasts to fill the resorption lacunae.
THYROID FUNCTION IN EUTHYROID SUBJECTS WITH AUTONOMOUS THYROID NODULES
Authors: EVERED D. C. , CLARK F. , PETERSEN V. B.
Published: March 2008

The biochemical abnormalities in euthyroid subjects with autonomous thyroid nodules have been defined. Seven subjects have been studied in detail. None were hyperthyroid and conventional tests of thyroid function were normal. The characteristic abnormalities were noted on scanning. The absent response to TRH demonstrated that pituitary TSH suppression was present in all subjects. A moderate elevation of serum triiodothyronine (T3) concentration, 1.89‐3.07 ng/ml, was noted. It is concluded that autonomous nodules in the euthyroid subjects studied are associated with elevated T3 levels sufficient to produce pituitary suppression but not high enough to be associated with the clinical manifestations of hyperthyroidism.
TESTICULAR FUNCTION IN MYOTONIC DYSTROPHY OF CHILDHOOD
Authors: HAMILTON W.
Published: March 2008

The histological appearances of testicular tissue obtained from six cases of dystrophica myotonica are shown. These appearances ranged from near normal to complete atrophy and hyalinization of the seminiferous tubules.

A method for the assessment of testicular steroid enzyme activity is proposed and has the advantage that preferential pathways of testosterone synthesis can be examined. Study of the enzyme activity in this testicular material showed that 17α‐hydroxylase is not an active testicular enzyme, that in three cases there was reduction in activity of the enzyme 17,20‐desmolase and in two cases there was reduced 17β‐reductase activity. Interstitium and tubules were not separately incubated in these experiments so that the defects observed cannot be associated with either tissue. However, since 17β‐reductase is normally more active in the tubules than interstitium, in the two cases where this enzyme was noted to be deficient, this could indicate failure of tubular enzyme activity.

The studies indicate that the rate of testicular atrophy in dystrophia myotonica varies from case to case and is not age‐related.
THE EFFECT OF HYPOTHALAMIC LUTEINIZING HORMONE RELEASING HORMONE (LH‐RH) ON PLASMA GONADOTROPHIN LEVELS IN NORMAL SUBJECTS
Authors: FRANCHIMONT P. , BECKER H. , ERNOULD CH. , THYS CH. , DEMOULIN A. , BOURGUIGNON J. P. , LEGROS J. J. , VALCKE J. C.
Published: March 2008

The release of gonadotrophin following the injection of synthetic LH‐RH (Hoechst) was studied in various physiological and experimental circumstances.

In the male, 25 μg of LH‐RH led to simultaneous release of FSH and LH prior to and during puberty. In adults, on the other hand, the same dose led only to an increase in LH while FSH levels remained unchanged. At higher doses there was FSH release and an increase in LH proportional to the amount of LH‐RH injected. When FSH was released the increase was clearly less than that of LH and often occurred considerably later.

In the female, 25 μg of LH‐RH led to a clear‐cut release of FSH and a small release of LH prior to puberty. After the onset of puberty the degree of response was inverted: the increase in LH was greater than that of FSH. In normally menstruating women the FSH and LH response was greater during the luteal phase than during the preovulatory phase. Treatment with non‐sequential hormonal contraceptives blocked FSH and LH release normally produced by the injection of 50 μg of LH‐RH. There was no effect when a dose of 100 μg was injected.

In post‐menopausal women, only LH rose following the administration of 25 μg of LH‐RH. After 5 days of treatment with 200 μg ethinyl oestradiol the same dose of LH‐RH led to simultaneous release of LH and of FSH.

From the above studies it can be concluded that the secretory response of the gonadotrophins to LH‐RH is influenced by the endocrine equilibrium and more particularly by the interaction of the gonadal steroids which can alter the synthesis and/or the release of the pituitary gonadotrophins.
PERIPHERAL RESISTANCE TO THYROXINE: A CAUSE OF SHORT STATURE IN A BOY WITHOUT GOITRE
Authors: SCHNEIDER GEORGE , KEISER H. R. , BARDIN C. W.
Published: March 2008

A euthyroid pubertal boy was investigated for short stature and was found to have an elevated serum thyroxine and delayed bone age. In spite of high thyroxine levels, there were no clinical signs of hyperthyroidism and kinetic studies revealed a normal rate of thyroxine metabolism. Plasma TSH levels were elevated but there was no goitre. Administration of up to 900 μg of triiodothyronine led to minimal changes in urinary hydroxyproline excretion, pulse rate and body weight. These observations indicate that this boy has a target organ insensitivity to thyroid hormones. When compared with other patients with this disorder, the studies further emphasize that this condition may have a variable clinical presentation. In addition, the extent of the target organ defect may not be evident from routine clinical and laboratory observations. The possible molecular basis of the defect is discussed.
THE LH RESPONSE TO LH‐RELEASING HORMONE IN CHILDREN WITH TRUE ISOSEXUAL PRECOCIOUS PUBERTY TREATED WITH CYPROTERONE ACETATE
Authors: KAULI R. , PRAGER‐LEWIN R. , KERET R. , LARON Z.
Published: March 2008

Fourteen girls and one boy with isosexual precocious puberty were submitted to LHRH stimulation tests, during and without therapy with cyproterone acetate. In addition, fourteen girls with isosexual precocious puberty not receiving any therapy were tested and served as controls.

It was found that cyproterone acetate induces suppression of the responsiveness of the pituitary gland to secrete LH on LHRH stimulation. Daily oral therapy was found to be more effective than the regimen of intramuscular depot injections.

These findings demonstrate that cyproterone acetate has an antigonadotrophic effect.
IODINE ORGANIFICATION DEFECT FOLLOWING TREATMENT OF THYROTOXICOSIS WITH ANTITHYROID DRUGS
Authors: HORTON P. W. , MILLAR W. T. , McLARTY D. G. , ALEXANDER W. D.
Published: March 2008

Two patients remained clinically euthyroid following treatment for thyrotoxicosis with antithyroid drugs in spite of persistently elevated thyroid radioiodine uptakes not suppressable by exogenous triiodothyronine. Perchlorate discharge tests showed a defect in the intrathyroidal organification of iodine. Circulating levels of thyroxine were normal. From our study of 105 patients treated for thyrotoxicosis with antithyroid drugs, apparent remission of thyrotoxicosis by this mechanism might occur in up to 2% of patients.
SPECIFIC CONTROL OF FOLLICLE STMULATING HORMONE IN THE MALE: POSTULATED SITE OF ACTION OF INHIBIN
Authors: BRAMBLE F. J. , HOUGHTON A. L. , ECCLES SHEILA S. , MURRAY M. A. F. , JACOBS H. S.
Published: March 2008

Serum luteinizing and follicale stimulating hormone concentrations were related to gonadal function, as reflected by sperm count and serum testosterone concentrations, in a group of men studied over 10 years after surgical correction of bilateral crytorchidism in childhood.

The results indicated that while all degrees of gonadal function occurred in these patients, the main adverse effect of crytorchidism was on spermatogenesis. In some of the patients with oligospermia and normal Leydig cell function there was an isolated increease f basal serum FSH concentrations, suggesting a specific iompairment of the testicular production of ‘inhibin’. Gonadotrophin releasing hormone (LHRH) tests in thesse patients were conpared to those in patients with normal basal gonadotrophins and to those with elevated basal LH and FSH concentrations. A selective exaggeration of the FSH response to expgenous LHRH in the group of patients with a monotropic elecation of FSH conventration suggests that ‘inhibnin’ modulates the secretion of FSH by an action on the pituitary rather than by modifying endogenous LHRH production by the hypothalamus.
FAILURE OF ADRENERGIC α AND β RECEPTOR BLOCKADE TO ELEVATE THE TSH AND PROLACTIN RESPONSE TO TRH IN HYPERTHYROIDISM
Authors: EPSTEIN S. , PIMSTONE B. L. , VINIK A. I. , McLAREN H.
Published: March 2008

The effects of adrenergic α and β receptor blockade on the thyrotrophin and prolactin responses to TRH were studied in groups of hyperthyroid patients who received either oral propranolol and phenoxybenzamine or intravenous propranolol and rogitine. The flat TSH and prolactin responses to TRH in the untreated hyperthyroid patients were not altered by oral or intravenous adrenergic α and β receptor blockade suggesting that catecholamines do not play a major role in the feedback suppression of TSH and prolactin in hyperthyroidism.
35S‐ANTITHYROID DRUG CONCENTRATION AND ORGANIC BINDING OF IODINE IN THE HUMAN THYROID
Authors: LAZARUS J.H. , MARCHANT B. , ALEXANDER W. D. , CLARK D. H.
Published: March 2008

35S‐methimazole (MMI), 35S‐carbimazole or 35S‐propylthiouracil (PTU) were given orally to fifty‐five patients at various times up to 12 h before surgical thyroidectomy. The amount of 35S radioactivity and labelled drug in thyroid and plasma samples was measured. Intrathyroidal inhibition of organic binding of iodine by MMI, carbimazole and PTU was measured after intravenous administration of 131I, 132I or 125I‐iodide. After administration of 35S‐carbimazole or 35S‐MMI the thyroid to serum (T/S) ratio of 35S radioactivity was greater in thyrotoxic glands than in non‐toxic adenoma tissue. 35S‐MMI was found in thyroid and plasma samples after administration of 35S‐carbimazole. The T/S 35S‐MMI was greater than 1 in most but not all patients. 35S radioactivity was also concentrated in the thyroid after administration of 35S‐PTU. In thyrotoxic glands there was an 80% inhibition of iodine organification in patients receiving MMI and 60% for those receiving PTU. It is suggested that carbimazole and MMI can be given once or twice daily in some patients but PTU would be less suitable for this dose schedule.

Drug treatment of thyrotoxicosis using the thiocarbamide group of antithyroid drugs renders patients euthyroid after a variable period of administration. This variation in response may reflect individual differences, either in the nature of the disease process or in the response to antithyroid drugs.

In this study we examine thyroidal levels of the thiocarbamide antithyroid drugs in thyrotoxicosis, non‐toxic goitre and ‘normal’ thyroid glands with particular emphasis on quantifying the effect of the drugs on inhibiting the organic binding of iodine within the gland.
ASSESSMENT OF ORAL GLUCOSE TOLERANCE DATA
Authors: BILLEWICZ W. Z.
Published: March 2008

Characteristics of the‘clinical value index’(Harding et al., 1973) are examined. It is shown that the definition of the index makes it unsuitable for the comparative evaluation of various methods of assessing the results of an oral glucose tolerance test.
RESPONSE OF PLASMA TESTOSTERONE, URINARY 17‐OXOSTEROIDS, OESTROGENS, AND ANDROSTERONE PLUS AETIOCHOLANOLONE TO HUMAN CHORIONIC GONADOTROPHIN IN DEXAMETHASONE‐SUPPRESSED MEN
Authors: METCALF M. G. , COWLES R. J.
Published: March 2008

The administration of human chorionic gonadotrophin (HCG) to dexamethasone‐suppressed men caused parallel changes in the concentration of plasma testosterone and in the urinary output of androsterone+aetiocholanolone, total 17‐oxosteroids and oestrogens. Discrepant results occurred in only four of the thirty‐seven men tested. With these exceptions, the response to HCG could be followed as well by measuring androsterone+aetiocholanolone, 17‐oxosteroid or oestrogen excretion rates as by following plasma testosterone levels. The most sensitive index of response was the rate of appearance of oestrogens in urine, and the next that of androsterone+aetiocholanolone.
CORTISOL BINDING CAPACITY AND OESTROGEN CONCENTRATIONS IN MATERNAL AND CORD PLASMA IN PREGNANCIES WITH NORMAL AND ANENCEPHALIC FETUSES
Authors: CAWOOD MARION L. , HEYS R. F. , OAKEY R. E.
Published: March 2008

The cortisol binding capacity of maternal and cord plasma samples obtained at delivery from fifteen women and their normal infants and from seven women and their anencephalic infants was measured at 4°C by a gel filtration technique. The concentration of oestrogen in these samples was measured by radioimmunoassay.

There was no significant difference (t test) between the cortisol binding capacity of peripheral plasma from women with normal infants (1.5±0.24 μmol/l, mean ± SD) and from those who delivered anencephalic infants (1.35 ± 0.30μmol/l), nor between the cortisol binding capacity of cord plasma from anencephalic infants (0.47 ± 0.04 μmol/l) and that of normal infants (0.37 ± 0.10 μmol/l). However, mean oestrogen concentrations in maternal and cord plasma from the pregnancies with an anencephalic fetus were significantly lower (P<0.01) than in the corresponding samples from normal pregnancy.

It is concluded that oestrogen concentrations in maternal and cord plasma in normal pregnancy at delivery are much greater than those required to account for the increase in plasma cortisol binding capacity. Since plasma cortisol binding capacity in pregnancy with an anencephalic fetus is not diminished, the reduced excretion of corticosteroids relative to normal pregnancy in this condition is unlikely to be due to alterations in cortisol metabolism associated with a lower plasma cortisol binding capacity.
CONGENITAL BILATERAL ANORCHIA IN CHILDHOOD: A CLINICAL, ENDOCRINE AND THERAPEUTIC EVALUATION OF TWENTY‐ONE CASES
Authors: AYNSLEY‐GREEN A. , ZACHMANN M. , ILLIG R. , RAMPINI S. , PRADER A.
Published: March 2008

An evaluation of twenty‐one boys, including a discordant pair of identical twins, is presented in whom bilateral anorchia was found with a negative family history and without history of breech presentation or of postnatal testicular trauma, torsion or orchitis. The most likely cause is prenatal testicular torsion. The incidence of the condition in our hospital is 1 in 177 cases of cryptorchidism. Prepubertal growth was normal beofore treatment, and testosterone replacement therapy allowed a normal pjubertal growth spurt and skeletal maturation. Although demonstrable basal urinary tstosterone was found in the subjects with a postpubertal bone age, most patients tested showed no increase after stimulation with human chorionic gonadotrophin. In the presence of a normal penis and scrotum, such findings, together with a high basal FSH and an increased response of plasma LH to LHRH, make surgical exploration unnecessary. In the rare patient who shows a positive but subnormal response of testosterone to HCG, Leydig cells are presumed to be present either ectopically or in rudimentary testes, and further surgical exploration is indicated.

Anorchia, or absence of the testes, may be congenital or acquired postnatally through trauma or testicular torsion. Several conditions may mimic congenital anorchia, the most common being virilization of a female fetus as a result of congenital adrenal hyperplasia, meternal androgen ingestion, or by maternal androgen secreting tumours.

Congenital anorchia has been said to occur in 1 in 20 000 male subjects (Bobrow & Gough, 1970) but despite this estimated prevalence there have been only eighty or so cases reported in the literature during the last 100 years. We have investigated twenty‐one additional cases, and wish now to report our observations. The reasons for the study are, first, that the number of cases, the largest series reported, allowsa thorough clinical and therapeutic evaluation; second, to report results on the testosterone response to human chorionic gonadotrophin administration and the luteinizing hormone and follicle stimulating hormone
FURTHER OBSERVATIONS ON POSTPARTUM OVARIAN REFRACTORINESS: EFFECT OF GONADAL STIMULATION IN WOMEN RECEIVING BROMOCRYPTINE
Authors: CANALES ELIAS S. , ZÁRATE ARTURO , SORIA JORGE , GONZÁLEZ JORGE , LEVINSON GENARO , FONIESCA EUGENIA
Published: March 2008

It has been reported previously that the administration of human menopausal gonadotrophins (HMG) to lactating and non‐lactating women from day 5 to day 9 postpartum elicited no significant elevation of urinary oestrogens or serum oestradiol within 15 days after delivery. In order to study further the role of prolactin on this ovarian refractoriness, five women receiving 7.5 mg of bromocryptine (CB‐154) daily were given HMG at a dose of 300 iu per day, from day 5 to day 10 postdelivery. In all women serum oestradiol and urinary oestrogens showed no significant elevation within the 2 weeks after delivery. Serum prolactine was elevated in all cases and fell to normal nonpregnant levels immediately after CB‐154 was administered. The suggestion that prolactin may possess antigonadotrophic activity at the ovarian level is not supported by the data presented here. The deficient ovarian response to gonadotrophin stimulation could be due to either the intraovarian effect of the high amounts of circulating steroids produced during gestation or to some unknown mechanism.
PLASMA DOPAMINE‐BETA‐HYDROXYLASE ACTIVITY IN PHAEOCHROMOCYTOMA
Authors: STONE RICHARD A. , LILLEY JOHN J. , GOLDEN JOEL
Published: March 2008

Plasma dopamine‐beta‐hydroxylase (DßH) activity, a marker of catecholamine secretion that occurs via exocytosis, was determined preoperatively in eight patients with phaeochromocytoma. Despite very elevated urinary catecholamine concentrations, mean plasma DßH activity was 32.6±3 u/1 and was not significantly different from apparently healthy subjects. Seven days after surgery, one subject exhibited a 60% postoperative decrease of enzyme activity. These results suggest that diffusion across plasma membranes is the predominant mechanism of catecholamine release from phaeochromocytomas. The postoperative change in one patient suggests tumour heterogeneity and that exocytosis may contribute to the process of catecholamine release in some patients.
HORMONAL AND METABOLIC RESPONSES TO GLUCAGON IN DIABETES MELLITUS
Authors: SIMPSON R. W. , HOCKADAY T. D. R. , ALBERTI K. G. M. M.
Published: March 2008

The metabolic and hormonal responses to glucagon (1 mg, subcutaneous) were studied in twelve diabetic and twelve non‐diabetic subjects. Diabetics showed a GH response, which although commencing slightly earlier, did not otherwise differ from that of the controls. There was the expected diminished insulin response to glucagon among the patients on oral agents. The GH response to glucagon in the diabetics began before there was any significant fall in blood glucose (BG). The hyperglycaemic response in the diabetics peaked later, was greater in amplitude and was more prolonged. In this group both pyruvate and lactate changes were delayed and diminished in amplitude. The diabetics showed a biphasic response of both acetoacetate and 3‐hydroxybutyrate to glucagon; a small transient significant rise in the first 2 h followed by a second rise after 3 h. In contrast the controls showed a significant fall in these metabolites during the initial 2 h, before a rise after 3 h. The significance of these hormonal and metabolic responses is discussed.
BROMOCRIPTINE SUPPRESSION OF PLASMA GROWTH HORMONE IN ACROMEGALY
Authors: DUNN P. J. , DONALD R. A. , ESPINER E. A.
Published: March 2008

Twelve acromegalic patients were studied in one or more of three protocols to establish the response of plasma growth hormone (hGH) concentrations to (a) a single oral test dose of bromocriptine, (b) incremental dose therapy from 10 mg/day to 40 mg/day over 4 weeks, and (c) sustained therapy with 20 mg/day over a 3 month period. Ten of the patients studied had previously been treated by yttrium implantation, external pituitary irradiation or surgical hypophysectomy. A high incidence of side effects including postural hypotension, hallucinations and peripheral vasospasm was noted reducing the numbers of patients completing the three protocols. Suppression of hGH concentrations was disappointing; significant reductions in hGH concentrations occurred in five of eleven patients in response to a single test dose of bromocriptine, and in only one of seven patients treated with the drug over a sustained period. An impression of clinical improvement was gained in one patient, but there was no associated reduction in plasma hGH concentrations. It seems likely that acromegalic patients who have failed to respond to conventional treatment may be more resistant to bromocriptine therapy.
COMPARISON BETWEEN THE PLASMA INSULIN AND GLUCOSE RESPONSES TO FIVE DIFFERENT INSULIN REGIMES IN DIABETIC PATIENTS
Authors: GOKAL R. , HARDING P. , TURNER R. C.
Published: March 2008

Diurnal plasma insulin and glucose concentrations were studied in six diabetic patients, each treated with five different insulin regimes. Subcutaneous soluble insulin was too slow and long acting for physiological replacement of the normal insulin response to meals, but the peak insulin levels were higher than the postprandial levels of normal subjects. Intramuscular insulin, though absorbed more quickly than subcutaneous insulin, was not clinically advantageous. Three rather than two injections of soluble insulin gave improved blood glucose control but two combined injections of short and medium acting insulins gave nearly as good results. A long acting insulin was needed to prevent raised plasma glucose levels overnight.
A NEW THEORETICAL DESCRIPTION OF THE BINDING OF THYROID HORMONES BY SERUM PROTEINS
Authors: PRINCÉ H. P. , RAMSDEN D. B.
Published: March 2008

A theoretical model is proposed which describes the binding of thyroid hormones to serum proteins in terms of easily determined parameters. Not only free hormone concentration but also the distribution of hormone among various binding sites may be computed. The mathematical approach is capable of dealing with models of differing complexity of binding from simple‘one binding site per protein molecule’systems to those involving‘negative co‐operativity'. The approach gives predictions of thyroid function parameters which are in good agreement with those observed in practice.
MEASUREMENT OF THE 24 HOUR INTEGRATED PLASMA CONCENTRATION OF GROWTH HORMONE, IN ASSESSING THE RESPONSE OF ACROMEGALIC PATIENTS TO TREATMENT
Authors: DAGGETT P. R. , NABARRO J. D. N.
Published: March 2008

The integrated concentration of growth hormone (ICGH) has been measured in fourteen acromegalic patients, and compared with the basal plasma growth hormone concentration (BGH). Seven patients were treated by trans‐sphenoidal pituitary surgery, and in these, similar percentage reductions of BGH and ICGH occurred after treatment. The other seven patients were treated with bromocriptine alone, and in these the percentage reduction of ICGH was significantly less than that of BGH. Measurements of basal plasma growth hormone concentration may be unreliable in assessing the response of acromegalic patients to treatment with bromocriptine. The ICGH can be measured easily on a single blood specimen obtained by continuous sampling over 24h, and may be more reliable for this purpose.