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We report a mutation (Y99C) in guanylate cyclase activator 1A (GUCA1A), the gene for guanylate cyclase activating protein (GCAP1), in a family with autosomal dominant cone dystrophy. Linkage analysis excluded all the known cone and cone-rod dystrophy loci, except the chromosome 6p21.1 region. This is known to contain the RDS gene, which is associated with dominant cone-rod dystrophy. Screening of the RDS gene by heteroduplex analysis and direct sequencing failed to demonstrate sequence changes in the coding region of this gene. The gene for GCAP1, a calcium binding protein which is highly expressed in photoreceptor outer segments, is also located in 6p21.1. It was screened for mutations, and all affected individuals showed a single base pair missense mutation (A-->G) at codon 99 in exon 2 of this gene generating a tyrosine-to-cysteine change in the GCAP1 protein. This change was absent from 206 unrelated normal controls. We propose that this change would at least disrupt the EF3handof GCAP1 thereby preventing calcium binding and consequently interfere with activation. The resulting effect on cGMP production would predictably modify the number of open cGMP gated cation channels, and could explain the ultimate demise of cone photoreceptor cells.

The recent determination of the genomic sequence of human caldesmon indicates that eight caldesmon mRNA species could be generated by selection of exon 1 or 1', exon 3a or 3ab and/or exon 4. We used reverse transcriptase PCR to determine which transcripts were produced in human, rabbit and sheep artery, vein, lung, intestine, kidney and liver. In all tissues the same three transcripts were present: exons 1'-2-3a-5-6...13, exons 1'-2-3a3b-5-6-...13 and exons 1'-2-3a3b-4-5-6...13. Exon 1 was not present and exon 4 was only present when exon 3b was also present. Three protein isoforms of caldesmon can be distinguished by electrophoresis on high-porosity 6% polyacrylamide gel: 130 kDa, 120 kDa and 70 kDa. The 70 kDa isoform lacks the sequence encoded by exon 3b. We investigated whether the two high-molecular-mass isoforms correspond to the presence and absence of exon 4 using an antiserum specific to the sequence encoded by exon 4. Western-blotting and immunoprecipitation experiments showed that both the 130 kDa and the 120 kDa isoforms were expressed with and without the exon 4 sequence. We therefore propose that the molecular-mass heterogeneity arises from additional first exons, possibly with separate promoter regions, which have not yet been characterized in the genomic sequence.

Placental steroid hormone production appears to be critical in maintaining pregnancy and possibly initiating parturition. Cytokines, produced by activated macrophages and decidua, are present during delivery, but their role in this process is not yet clear. To our knowledge, only one recent study, which used JEG-3 choriocarcinoma cells as an in vitro model, has evaluated the possibility that cytokines might affect placental steroidogenesis. Our current study reports observations on the effect of macrophage conditioned media (MCM, known to contain several cytokines) on the synthesis of progesterone and estradiol by term, normal, human placenta. Macrophage conditioned media significantly decreased progesterone (36 percent) and increased estradiol (76 percent) production by short-term placental organ cultures. These results suggest that macrophage secretory products might significantly alter placental steroidogenesis which could make them important factors in the physiology of parturition.

Primary gonadal failure frequently occurs in male patients with serious illness. This has suggested that activation of the immune system may affect the endocrine function of the testis. Most previous studies have evaluated the effects of individual cytokines on testosterone (T) production but with conflicting results. The present study was performed to compare the effects on Leydig cell function of a mixture of cytokines found in macrophage conditioned media (MCM), with that of individual recombinant cytokines. The MCM was found to contain an acid stable, heat labile, 16.5 kD factor(s) which significantly decreased the production of testosterone (T), dihydrotestosterone (dHT), adenosine 3':5'-cyclic monophosphate (cAMP), and guanosine 3':5'-cyclic monophosphate (cGMP). The MCM had no effect on the specific binding of human chorionic gonadotropin (hCG) but decreased the activity of 3-beta-hydroxysteroid dehydrogenase (3-beta-HSD) (a regulated Leydig cell enzyme). Neither tumor necrosis factor alpha (TNF alpha) interleukin 1 alpha (IL1 alpha), interleukin 1 beta (IL1 beta), interleukin 2 (IL2), interleukin 6 (IL6), or human interferon alpha,beta (IFN alpha,beta) had a similar effect. These results show that the cytokines or other factor(s) contained in MCM are potent regulators of T production, which could be important in understanding the low serum T levels associated with serious illness.

Clinical observation of patients with congenital growth hormone (GH) deficiency and Laron-type dwarfism suggests that factors such as GH or insulin-like growth factor 1 (IGF-1) might in addition to androgens, be needed for normal phallic growth. We speculated GH or IGF-1 might have direct actions on genital tissues and performed the present study to evaluate the in vitro effects of GH and IGF-1 on cultured neonatal foreskin fibroblasts. Cells derived from foreskins of normal newborns were studied between cell passages 6 and 15. Serum-free media with and without 100 ng/ml GH, IGF-1, or both were added 24 hours prior to and at the time of study. To determine the activity of 5-alpha-reductase (5-alpha-R), 3H-testosterone (T: 2 nM) was added, and 5-alpha-R activity was calculated as femtomoles 3H-dihydrotestosterone and 3H-androstanediol produced/microgram DNA/hour. Androgen receptor (AR) binding was determined by the addition of 3H-dihydrotestosterone (dHT; 0.03125-0.5 nM) in the presence and absence of a 200-fold excess of unlabeled dHT. Specific binding was used in Scatchard analysis for determination of AR number (Bmax) and binding affinity (Kd). The rate of DNA synthesis was determined by incorporation of 3H-thymidine (3H-Thy) into trichloroacetic acid-insoluble material. DNA and protein content were determined on cell lysates. IGF-1, but not GH, had proliferative effects (significant increases in the rate of 3H-Thy incorporation, DNA, and protein content) but no effect on 5-alpha-R activity, Bmax or Kd.(ABSTRACT TRUNCATED AT 250 WORDS)

In a vaccination and laboratory study, two dried smallpox vaccines (designated P and Q) were tested at intervals of 4, 8, 16, and 32 weeks after storage at both 37 degrees C and 45 degrees C. Vaccine P was also tested after 64 weeks at these temperatures and gave 100% successful vaccination rates after all periods of storage at both temperatures. Vaccine Q deteriorated within four weeks, rapidly at 45 degrees C and less rapidly, but very substantially, at 37 degrees C. There was no clear evidence of the cause of this deterioration, but there was a suggestion of denaturation of some of the samples stored at the higher temperature. So far as could be ascertained, the laboratory results-rabbit skin scarification tests and chorio-allantoic membrane pock counts-ran parallel with the vaccination success rates. The pock count was found to be the more accurate method of laboratory titration. Vaccine P as used in the trial was not an exceptional batch.Vaccines which give a pock count of 10(8) infective units per ml will give the highest possible rate of successful primary vaccinations.A statistical note on the trials is given in an annex.

As in an earlier study, the authors have endeavoured to review the world incidence of poliomyelitis on the basis of the available statistical information (official notifications of cases and deaths) and to compare these data with data received from various sources regarding the prevailing viruses.It is certainly not yet possible to establish side by side the cartography of actual poliomyelitis cases and that of the prevalence and distribution of the polioviruses. However, it may not be too early to make a start in this direction.In Africa there was a rise of about 40% in the number of poliomyelitis notifications. Part of this increase is probably due to improved reporting. Characteristic epidemics were observed in the west (Senegal, Cameroons under French administration), as well as in the east (Sudan, Kenya, Tanganyika, Northern and Southern Rhodesia, Union of South Africa).In America the most outstanding outbreaks were observed in Alaska, in Wyoming, Nebraska, Iowa, Florida, and California, and all round the Caribbean Sea (Costa Rica, Guatemala, Haiti, Jamaica, Puerto Rico, Trinidad).In the Asiatic countries the number of notifications was generally of the same order as in 1953.The incidence also declined in Europe, in spite of the fact that Greece was affected by the most serious epidemic recorded in its history. Other outbreaks were recorded in Finland, Switzerland, and Austria, where the incidence had also been high in the previous year. An increase was also noted in Scotland.Finally, in Oceania, poliomyelitis took on epidemic proportions in Australia (in the territory of the Federal Capital and in the States of Victoria and Western Australia) and in the Hawaiian Islands.

In the ten years since attenuated poliovirus was first administered to man for immunization against poliomyelitis, a vast body of experience has grown up and an attempt can now be made to assess the potentialities of oral poliovirus vaccine. The author of this paper seeks to answer two main questions: how safe are the strains now under study, and is oral vaccine effective in practice under the different conditions in which it may be used?From the information gained in large-scale trials involving a total of nearly 70 million people, he concludes that where poliomyelitis is predominantly a disease of infancy and early childhood the vaccines now available are safe both for the individual and for the community. The Sabin strains appear also to be safe for use in areas where the disease affects older children and adults; there is still not enough information to permit final conclusions to be drawn as to the safety of the Koprowski and Lederle strains in such areas.The evaluation of data on the efficacy of rural vaccines is beset with many problems, but the evidence of serological conversion rates suggests that, with one exception, there are no striking differences in efficacy between any of the strains when used in monovalent vaccines. However, 100% conversion cannot be expected in all circumstances from any oral vaccine given once only; repeated administration is clearly necessary, although it is still too early to say what the best vaccine schedule may be in any particular set of circumstances.While the problems yet to be solved are legion, great progress has nevertheless been made in the past decade, and the author looks forward to a steady extension of the use of live poliovirus vaccine and even to the eventual possibility of the eradication of poliomyelitis.

This article describes the evolution of international co-operation for the control of epidemic influenza, from the founding of the United States Armed Forces Commission on Influenza in 1941 to the present network of influenza centres designated by WHO in 42 different countries. The technical problems of dealing with this disease on a worldwide scale are indicated, and their bearing on the development of the WHO influenza programme discussed. Suggestions are made for the simplification and co-ordination of the system on which epidemiological information is compiled, and the need for speed in both its collection and its dissemination is emphasized.

The incidence of poliomyelitis throughout the world is outlined on the basis of official statistics-in many cases necessarily provisional or approximate-augmented by information from wider and unpublished sources. Available reports on the virus types responsible for poliomyelitis outbreaks in recent years are also summarized.A rise in apparent incidence occurred in the following countries in 1953: Africa-Angola, Egypt (largely due to improved reporting), Middle Congo (French Equatorial Africa), Morocco (French Zone), Ruanda-Urundi, Tanganyika, Tunisia, Union of South Africa, and Upper Volta (French West Africa); America-Argentina, Brazil, Canada, Colombia, El Salvador, Greenland, Mexico, Nicaragua, and Uruguay; Europe-Austria, Finland, France, Greece, Italy, Norway, Republic of Ireland, Saarland, Sweden, Switzerland, Trieste (British/United States Zone), Turkey, United Kingdom, and Yugoslavia. The epidemics in Canada and Sweden were the most severe ever recorded in the two countries. The incidence decreased markedly in: Africa-Kenya, Mauritius, Southern Rhodesia, and Uganda; America-Chile (probably), Cuba, and the USA; Asia-Cambodia, Ceylon, India, Israel, Lebanon, Philippines, and Thailand; Europe-Belgium, Denmark, Federal Republic of Germany, Luxembourg, the Netherlands, Portugal, and Spain; Oceania-Gilbert and Ellice Islands, Hawaii Islands, and New Zealand.While data on virus types are insufficient for any definitive conclusions to be reached as to responsibility for poliomyelitis outbreaks, it would appear that all three types are widely distributed, while in the selected areas where polioviruses have been typed, type 1 virus has been isolated the most frequently.

In 1957 the World Health Organization arranged a survey of horse and swine sera in a number of countries in order to gain information on the role and importance of animals in the epidemiology of influenza. The veterinary services of the countries concerned were requested to obtain blood specimens from these animals, if possible both before and after the human pandemic of Asian influenza. This paper reports on the results of haemagglutination-inhibition and complement-fixation tests performed on these sera in WHO Influenza Centres and other collaborating laboratories.It is apparent from these results that the Asian (A2) strain can cause natural inapparent infection in horses and swine. Equine influenza caused by the A-equi strain is also present in many countries from which it had not been previously reported, and infection in pigs with the A-swine strain, long known in the USA, has now been recorded in at least two European countries.In a concluding section, the findings in this survey are related to other observations on the position of animals in influenza epidemiology, and future research needs are outlined.