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These results have the potential to lead to novel therapeutic strategies for the treatment of human disease. Box , Grants and Contracts Aurora, Co Timing: Fiscal Year ; Project Start JAN; Project End AUG Summary: This is a request for an additional five years of funding for "Cytotoxic Mechanisms in Cutaneous Disease" which has been funded to sixteen years to study the mechanisms of immunologic damage to keratinocytes and melanocytes, a central component in important skin diseases such as photosensitive lupus erythematosus, vitiligo, erythema multiforme, toxic epidermal necrolysis and lichen planus.

We have found that the epidermis is intrinsically resistant to immunologic cytotoxicity, due in large part to resistance of basal keratinocytes and melanocytes to apoptosis induced by immunologic triggers. We hypothesize that this resistance to apoptosis in undifferentiated keratinocytes and melanocytes is maintained by "survival" signals provided by growth factor activation of receptors and by extracellular matrix activating cell surface integrins.

We propose to test the effect of growth factor and integrin blockade on the susceptibility of melanocytes and keratinocytes to induction of apoptosis by ultraviolet radiation UVR , ionophore, anti-Fas, and cytokines. Using combinations of blocking, rescue and transfection experiments, we will verify that survival signals in melanocytes and keratinocytes are transmitted through ras activation, and directly regulate expression of important proteins which control apoptosis, such as bc, and perhaps bc1-x, Bax and Bad.

We will also study regulation of these important proteins following nuclear translocation of p53, and important trigger of apoptosis induced by UVR. This proposal addresses the molecular and cellular biology of a fundamental characteristic of the basal layer of the epidermis: its intrinsic resistance to immunologic cytotoxicity. Although these anti- apoptotic defenses protect the skin from unwanted effects of inflammation, they may also allow favor survival melanoma and squamous cell carcinoma.

Virtually nothing is known about the cellular and molecular mechanisms that control development and innervation of Merkel cells. My advisor, Prof. Grim, and his collaborators have shown that Merkel cells are derived from the neural crest and that their precursors migrate in the ventrolateral migratory pathway in the subectodermal space. The proposed work is designed to elucidate some of the roles growth factors play in the development of quail neural crest cells into Merkel cells. In Aim 1, Merkel cells in culture will be characterized at the ultrastructural level and compared to Merkel cells in the intact organism.

In Aim 2, the expression Studies 9 during embryonic development of pertinent growth factor receptors by Merkel cell precursors and maturing Merkel cells will be elucidated by indirect immunohistochemistry and in situ hybridization.

By use of the neural crest cell colony assay that has been developed in Prof. Sieber-Blum's laboratory, I propose in Aim 3 to assess the role of pertinent growth factors as determined in Aim 2 in the survival, proliferation and differentiation of Merkel cells. The proposed work has relevance to human neurological disease. In individuals with anhidrotic ectodermal dysplasia, and in the corresponding mouse model, Tabby, there are no Merkel cells Srivastava et al. This is most likely due to down-regulation of the EGF receptor.

In vitiligo, Merkel cells as well as melanocytes are lost Kumar Bose, A disrupted neurotrophin-3 gene in mice causes perinatal loss of Merkel cells and other neurodegenerative symptoms Airaksinen et al. Merkel cell carcinoma small, intermediate and trabecular types is a relatively frequent tumor Schmidt et al. Insights into the mechanisms that regulate normal Merkel cell development may prove useful in future approaches for the prevention or treatment of neurological disease. This skin disease may be related to the fact that the immune system attacks cells that give the skin its color.

Our goal for this proposal is to narrow the susceptibility region and to identify the susceptibility gene. We will achieve this by iterative reduction in the size of the chromosomal region. To improve the power of the study, specific aim 1 is to first augment our current data with new data, identified from our ongoing SLE genetic linkage projects. We will then narrow our previously identified susceptibility region in two steps.

First, in specific aim 2, we will choose microsatellite markers to form a cM map across the current susceptibility region and analyse these data using genetic linkage methods. Second, in specific aim 3, we will choose single nucleotide polymorphism SNP markers to form a 0. In the final step, specific aim 4, we will search the public databases for SNPs in genes known to be located in the narrowed susceptibility region established by specific aim 3 and to analyse these using linkage disequilibrium methods.

Specific aim 5 is to sequence the gene to find the causal mutations. We ascertained families with European 10 Vitiligo American ancestry, multiplex for SLE and each family has at least one member afflicted with vitiligo. Since autoimmune diseases are thought to share some of their genetic origins, decreasing sample heterogeneity would increase the power to identify the susceptibility gene s.

As the presence of vitiligo in the family was used as a pedigree ascertainment criterion, and there was significantly higher risk associated with developing vitiligo among the family members affected with SLE compared to non-SLE family members, we postulated the following hypotheses: SLE and vitiligo may share common autoimmune genetic determinant s for their pathophysiology. Alternatively, we may assert that there are genes that lead primarily to develop SLE, which may also modify the risk of developing vitiligo, at least among the ascertained families. Our preliminary results support the hypothesis that SLE and vitiligo may share common genetic determinant s 1.

This very common skin affliction is of great significance among dark skinned people in the United States and worldwide. In many countries and societies people with vitiligo are treated as outcasts. We propose that the defenses of melanocytes against cell death are overcome in vitiligo, and must be restored during vitiligo repigmentation. We hypothesize that Insulin-like Growth Factor 1 IGF-1 is a critical mediator of melanocyte function, stimulating melanocyte movement and proliferation and promoting melanocyte survival by maintaining anti-apoptotic defenses.

This proposal will define the IGF-1 anti-apoptotic defenses of melanocytes. Specific Aim 1 will demonstrate that IGF-1 maintains the resistance of human melanocytes to apoptosis and will determine which anti-apoptotic proteins are controlled by IGF Specific Aim 2 will determine which of these IFG-1 effects are mediated through the Ras signaling pathway. Specific Aim 4 will determine whether intergrin receptors and the IGF-1 receptor act synergistically to control anti-apoptotic defenses in melanocytes.

These project is innovative because it: i. Applies modern knowledge of the molecular control of apoptosis and cell death to the study of melanocyte survival, a fundamental biologic feature relevant to human vitiligo, and ii focuses attention on the role of IGF-1 in melanocyte biology. IGF-1 is a powerful mediator of melanocyte function and mediates crucial survival mechanism in other types of cells.

The experiments proposed in this RO3 grant will provide the preliminary data for a future RO1 on IGF-1 as a survival factor in vitiligo. The detailed mechanistic studies of IGF-1 control of melanocyte survival will provide a proper basis for questions concerning the relative role of IGF-1 in melanocyte destruction in vitiligo, and of melanocyte survival during repigmentation of vitiligo.

Box , Grants and Contracts Aurora, Co Timing: Fiscal Year ; Project Start SEP; Project End AUG Summary: Generalized vitiligo is a common, non-contagious disorder, characterized by progressive patchy loss of pigmentation of the skin, overlying hair, oral mucosa, and occasionally eyes, due to progressive loss of pigment forming melanocytes in the affected areas Vitiligo is thought to be autoimmune in origin, and frequently is associated with other autoimmune disorders.

The prevalence of vitiligo is approximately 0. Vitiligo is most significant in dark-skinned populations, for its pigmentary disfigurement produces social stigmatization and is often confused with leprosy or other socially terrifying infectious diseases. But it can be a devastating disorder to those affected in any population. In preparation for this study, we conducted a survey of vitiligo patients in the United Kingdom, the largest ever done, thereby ascertaining a large cohort of families with vitiligo. Further, one or more susceptibility loci appears to account for an apparent autosomal dominant inheritance of vitiligo.

However, the major gene s in these families does not account for the total increased risk for vitiligo in relatives, suggesting that susceptibility alleles with lower penetrance at the same or different loci are important in other families. These results suggest a mixed model for the inheritance of vitiligo, which has also been reported for many other complex disorders. The proposed studies will combine the UK vitiligo family cohort with a similarly sized vitiligo family cohort in the USA.

Utilizing these resources, and polymorphic markers spaced at approximately 10 cM intervals throughout the genome, we proposed a two-phased approach to mapping vitiligo susceptibility loci. The specific aims are: 1 Map autosomal dominant vitiligo susceptibility loci by parametric linkage analysis in families with 4 or more affected relatives; and 2 map other vitiligo susceptibility loci by parametric linkage analysis in families with 4 or more affected relatives; and 2 map other susceptibility genes using non-parametric linkage analysis in affected sib pairs.

This rational and comprehensive approach will provide the greatest likelihood of mapping vitiligo susceptibility loci, thereby accelerating the identification, and the molecular, cellular, clinical, and epidemiological characterization, of the disease genes. BPR melanocytes are genetically sensitive due to a defect in their SOD and GSH levels caused by the barring gene and die prematurely from oxygen radical toxicity.

WL chickens carry the dominant white gene in addition to the barring gene and have a further reduction of SOD and their 12 Vitiligo melanocytes die much earlier than the BPR melanocytes. Some forms of human vitiligo may be caused by a similar mechanism. The specific aims are focused to further test this hypothesis and to elucidate at the molecular gene level why SOD and GSH levels are low in the mutant birds and to determine the role that the keratinocytes may play in these vitiliginous avian models.

Comparisons will also include other species. Compare and assess differences in CT SOD between the 3 bird types by expression of the enzyme under a single promoter. If the down regulation of GSH is determined to be caused by one or more of the enzymes involved, then a molecular characterization of the mutant gene will be performed in the same manner as that for the SOD gene.

Enzymes associated with melanogenesis and cell death will be analyzed cytochemically in the melanocytes. In all cases, the JF will serve as a control. GSH-peroxidase under normal and oxygen radical stress conditions. The measurements of the above parameters of the feather tissue, which predominately includes the keratinocytes and few melanocytes, has already been performed. These disorders include solar lentigines liver spots , vitiligo, freckles, and darkening of grafted skin.

Additionally, the desire for skin whitening cosmetics is common in various cultures around the world. Current treatments lightening skin are usually topically applied harsh chemicals, such as hydroquinone or its derivatives, but overall lack reliability in efficacy and have issues of safety. We have isolated and characterized a unique and potent skin lightening protein from hyperpigmented xenographs. This natural agent provides a new approach to blocking the formation of melanin, the cause of hyperpigmentation. In both in vitro and in vivo models, the protein effectively inhibits the activity of tyrosinase, a marker for hyperpigmentation.

A small fragment of the protein has been identified that effectively mimics the in vitro activity. The goals of these Phase I studies are to demonstrate in vivo effectiveness of the fragment and to identify a small series of peptides for optimization and clinical evaluation in Phase II. Burn victims, the aging and other individuals with skin hyperpigmentation exist by the millions throughout the world. This would be a significant market. The cosmeceutical uses expand the potential many fold. Cutaneous pigmentation protects a person from various environmental assaults, like ultraviolet light, as well as potential cellular injury, that can cause cancer and aging of the skin.

Loss of skin pigmentation can result in cancer, aging, and compromised immunity of the skin as well as psychological and social problems of self- esteem and personal interactions. This disease can be financially and socially devastating for the individual, in addition to it compromising the productivity in the workplace. The general goal of this proposal is to assess the pathological effects of phenolic and catecholic derivatives on melanocytes.

Specifically, we propose to assess the relative cytotoxicity, the interaction with tyrosinase, and the generation of toxic free radical products within melanocytes exposed to various phenolic and catecholic derivatives. In addition, we will determine whether the response of these molecules is altered in vitiligo melanocytes demonstrated to be more susceptible to cytotoxicity. The technology for appropriate delivery of peptide antigens is still new and undergoing rapid development, and no consensus methodology exists.

In addition, while CTL responses against pathogens and tumors have been stimulated by many of these methods, there have also been numerous failures. One important factor in the use of peptide antigens is that their affinity for the presenting MHC molecule will influence the level at which they are presented by APC in order to stimulate a CTL response, as well as their display on an infected cell or a tumor.

In this regard, a large set of peptide antigens that are the subject of a number of clinical trials are those that have been defined as CTL targets on human melanoma cells. In addition, reproducible and generally accepted criteria for the development of effective CTL in response to vaccination are not well established. Therefore, it is important to develop means of quantifying CTL activity that bear a direct relationship to therapeutic efficacy. Comprehensive evaluation of these issues in vaccine delivery methodology in early stage clinical trials is prohibitive because of the difficulty in enrolling significant numbers of patients in many different protocols and comparing results obtained by the use of different methods.

Therefore, development of appropriate preclinical models is a desirable goal. The specific aims of this proposal will lead to the definition of methodology to measure both CTL number and avidity, and the use of this methodology to evaluate the importance of these parameters in effective tumor-specific immune responses.

In addition, the impact of peptide affinity for MHC molecules on both the stimulation of CTL and their effectiveness in tumor destruction will be examined systematically. These issues will be addressed through the development of a preclinical model that will allow the evaluation of effective immune responses to peptide antigens that are presented by human class I MHC molecules. Although the pathogenesis of vitiligo is still poorly understood, evidence suggests that in many cases vitiligo is an autoimmune disorder and melanocyte loss is the result of an immunological response.

The mutant Smyth line chicken is an accepted animal model for autoimmune vitiligo. Studies 15 Chickens from this line develop a spontaneous, vitiligo-like, postnatal loss of melanin producing pigment cells melanocytes in feather and choroidal tissue between 6 and 14 weeks of age. Like many autoimmune diseases, SL vitiligo is a multifactorial disorder, involving an inherent melanocyte defect, an immune system component, and an environmental component. Studies examining the basic defect manifested within the SL melanocyte describe the presence of a competent pigment system at hatch.

Prior to visible signs of vitiligo, the earliest abnormality detected within SL melanocytes are irregularly shaped melanosomes containing pigmented membrane extensions, hyperactive melanization, and selective autophagocytosis of melanosomes. These aberrant processes precede the degeneration of SL melanocytes in vivo and in vitro but are not sufficient to cause the expression of vitiligo without a functioning immune system.


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Mechanisms underlying the dysfunction, progressive degeneration, and eventually, immune recognition and destruction of SL melanocytes are poorly understood. These studies will be carried out using feather tissue and melanocyte cultures from SL chickens that are highly susceptible to the development of vitiligo, parental BL chickens that are susceptible to the development of vitiligo but rarely express vitiligo, and LBL chickens that are vitiligo resistant. The knowledge that will be gained from these studies regarding the underlying mechanism of the SL melanocyte's inherent susceptibility for degeneration and autoimmune destruction.

Vitiligo, characterized by partial or complete loss of skin pigmentation and alopecia areata, a chronic inflammatory hair disorder are two such diseases. Interestingly, while certain autoimmune skin disorders such as bullous diseases result from reactions limited to specific components of skin, vitiligo and alopecia often manifest in association with other autoimmune diseases. This suggests that immune tolerance to self-antigens on pigment producing melanocytes and cells in the hair follicles is broken relatively easily.

The molecular identity of these antigens and the role of humoral vs. Biochemical and immunocytochemical techniques employed to identify antigens recognized by autoantibodies in the sera of patients have failed to yield definitive knowledge of target antigens in these disorders. Similarly, methodological limitations in analyzing and characterizing T lymphocytes in vitro have precluded extensive studies on the role of T cells in the pathogenesis of vitiligo and alopecia.

Recent developments in the field of human tumor immunology provide an opportunity to overcome these limitations on molecular identification of targets for immune responses in autoimmune skin disorders. Together with recent studies that showed the presence of HLA class II-restricted CD4 T cells to tumor antigen recognized by CD8 cells, these observations from SEREX analysis reinforce the concept of simultaneous presentation of self-antigens to humoral and cellular immune systems. This raises the possibility that SEREX analysis with sera from patients with autoimmune skin disorders could allow identification of tissue-specific antigens recognized by antibodies and T cells.

Molecular identification of the array of antigens targeted for immune response in these diseases will help delineate mechanisms of their pathogenesis. We propose to generate cDNA expression libraries from pooled cultures of neonatal melanocytes obtained from different racial backgrounds and pooled hair follicles microdissected from normal scalp biopsies.

These expression libraries will provide a source of unlimited supply of tissue-specific gene products to begin dissecting immune responses by SEREX analysis. It is expected that such analysis will allow identification of targets for both antibody and T cell responses in vitiligo and alopecia areata. Especially for teenagers, the associated change in appearance can be devastating. In recent years, it has become clear that the expansion of lesions is associated with an autoimmune response specifically targeting melanocytes, the pigment-synthesizing cells of the skin.

Genes associated with the development of vitiligo support the concept, that vitiligo should be considered a hereditary autoimmune disorder. What remains to be explored is the factors that contribute to the onset of disease, as prevention or intervention should preferably take place at this stage. Patients frequently experience skin trauma prior to the onset of new lesions. Precipitating factors include mechanical injury, contact with bleaching phenols, and overexposure to UV light. Such factors impose stress on the skin, and induce the expression of stress proteins to protect affected cells from undergoing apoptosis.

These same stress proteins also serve immunogenic functions, evoking an immune response to the cells from which they are derived. The hypothesis underlying the current project is that stress proteins mediate the initiation of an immune response to melanocytes. Stress proteins aberrantly expressed in actively depigmenting vitiligo skin including HSP27 and HSP70 will be assessed for their contribution to activation of dendritic cells DCs , particularly in relation to recently discovered cytotoxic effector functions.

Molecules mediating such effectormechanisms will be explored, as will accompanying receptor molecules on targeted melanocytes. Since expression of molecules involved in T cell recognition of melanocytes is altered following stress, the consequences for T cell responses will also be explored. In vitro results will be correlated to gene expression observed in depigmenting vitiligo skin and in skin maintained under stress. Finally, a mouse model will be generated that incorporates knowledge acquired in melanoma research, where vitiligo frequently develops in response to successful tumor immunotherapy.

Pelage depigmentation serves as areadout for immune Studies 17 responses directed to melanocytes after immunizing mice with and without stress proteins, to define the role of stress proteins in an in vivo model. The same model will be of use to test the efficacy of therapeutic modalities to be developed for vitiligo in the future. This search gives you access to fulltext articles.

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TABLE OF CONTENTS.

Source: Journal of the American Academy of Dermatology. Source: Archives of Dermatology. Source: American Journal of Human Genetics. Epub April Source: Trends in Immunology. Source: The British Journal of Dermatology. Source: Pediatric Dermatology. Source: The Journal of Dermatology. Source: International Journal of Dermatology. Source: Neoplasma. Source: Minerva Stomatol. Source: Archives of Dermatological Research. Epub March Source: Acta Dermato-Venereologica.

Source: Clinical and Experimental Immunology. Source: The Journal of Investigative Dermatology. Source: Autoimmunity. Source: Pediatric Nephrology Berlin, Germany. Author s : Schallreuter KU. Source: Ann Ophthalmol. No Abstract Available. Author s : Jimbow K. Author s : Mutalik S.

Source: Trop Doct. Author s : Picardi A, Abeni D. Source: Plastic and Reconstructive Surgery. Author s : Achauer BM. Source: Mycoses. Author s : Zaima H, Koga M. Source: Lancet. Source: Mymensingh Med J. Author s : Dogra S, Parsad D. Author s : Verma S, Kumar B. Kiniwa et al. Cancer Res.

Author s : Fodor J. Source: Cancer Research. Source: Dermatology Basel, Switzerland. Source: Biochimica Et Biophysica Acta. Author s : Radmanesh M. Source: Yonsei Medical Journal. Part II: Leukoderma due to cosmetics and bleaching creams. Author s : Fisher AA. Source: Cutis; Cutaneous Medicine for the Practitioner. Part III: Occupational leukoderma.

Source: Indian Pediatrics. Source: Clinical and Experimental Dermatology. Source: J Formos Med Assoc. A case report. Source: Clin Exp Rheumatol. Author s : Handa S, Dogra S. Author s : Gupta S, Kumar B. Epub October Author s : Kent G, al-Abadie M. Author s : Lanigan SW. Source: Eur J Dermatol. Source: Journal of Neurology.

Report of one case. Source: Thyroidology. Source: Dermatologica. Source: Journal of Dermatological Science. Source: Journal of Tropical Pediatrics. Studies on the outcome of exchanging biopsies from vitiliginous skin to normal, pigmented skin and vice versa. Author s : Falabella R. Author s : Antoniou C, Katsambas A. Source: Drugs. American Academy of Dermatology. Source: The Journal of Experimental Medicine. Author s : Kopera D.

Source: Clinics in Dermatology. Source: Disease Markers. Source: Immunology Letters. Author s : Juhlin L. New data, more enigmas.

Signs and symptoms

Author s : Nordlund JJ. Author s : Kossard S, Commens C.


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Source: Journal of the Royal Society of Medicine. Author s : Iverson MV. Author s : Ichimiya M. Source: Biochemical and Biophysical Research Communications. Author s : Taieb A. Author s : Olasode OA. Source: Niger J Med. A placebo-controlled double-blind study. Source: Genet Couns. Source: Journal of Cutaneous Pathology. Author s : Moellmann G. Author s : Honigsmann H, Ortel B. Source: Photodermatol. A model for human vitiligo. Author s : Thissen M, Westerhof W. Author s : Bhargava RK. Author s : Rodermund OE.

Author s : Moore MH. Source: The Journal of Craniofacial Surgery. Source: J Periodontol. Author s : Shaffrali F, Gawkrodger D. Results of a questionnaire among dermatologists in The Netherlands. Source: Acta Med Croatica. Author s : Yu HS. Source: Journal of Biomedical Science. Author s : Mulekar SV. Source: The Journal of Pathology.

Author s : Burns DA. Source: Indian J Dermatol. Source: Dermatologic Clinics. Source: American Journal of Ophthalmology. Part I. Cosmetics, systemic coloring agents, and corticosteroids. Part II. Less commonly used and experimental therapies. Meta-analysis of the literature.

Source: Contact Dermatitis. Source: J Occup Med. Author s : Das M, Tandon A. Author s : Camacho F, Mazuecos J. Source: J Drugs Dermatol. Source: J Trop Med Hyg. Author s : Roelandts R. Source: Journal of Child Neurology. Source: The American Journal of Medicine. A case-control study. Source: Psychotherapy and Psychosomatics. A pilot study. Source: Hormone Research. Author s : Sardi JR. Author s : Tanghetti EA. Erratum In: Acta Derm Venereol. Source: Acta Dermatovenerol Croat. Source: The American Journal of Dermatopathology.

Author s : Ishii M, Hamada T. Author s : Skolnick AA. The combination of vitiligo vulgaris with somatic and psychomotor retardation, cleft palate and facial dysmorphism: a distinct entity? Source: Acta Medica Austriaca. An elective treatment for segmental vitiligo. Source: American Journal of Clinical Dermatology.

Source: Human Genetics. Source: Clinical Immunology and Immunopathology. The IBIDS contains over , scientific citations and summaries about dietary supplements and nutrition as well as references to published international, scientific literature on dietary supplements such as vitamins, minerals, and botanicals. An advanced search allows you to retrieve up to fully explained references in a comprehensive format.

IBIDS is produced by the Office of Dietary Supplements ODS at the National Institutes of Health to assist the public, healthcare providers, educators, and researchers in locating credible, scientific information on dietary supplements. Motte speaks of a case at sixty-one; Ryan and others, at fifty-five, sixty, and sixty-five; Parry, from sixty-six to seventy seven; Desormeux, from sixty to seventy-five; Semple, at seventy and eighty seven; Higgins, at seventy-six; Whitehead, at seventy-seven; Bernstein, at seventy-eight; Beyrat, at eighty-seven; Haller, at one hundred; and highest of all is Blancardi's case, in which menstruation was present at one hundred and six years.

In the London Medical and Surgical Journal, , are reported cases at eighty and ninety-five years. In Good's System of Nosology there are instances occurring at seventy-one, eighty, and ninety years. There was a woman in Italy whose menstrual function continued from twenty-four to ninety years. Emmet cites an instance of menstruation at seventy, and Brierre de Boismont one of a woman who menstruated regularly from her twenty-fourth year to the time of her death at ninety-two. Strasberger of Beeskow describes a woman who ceased menstruating at forty-two, who remained in good health up to eighty, suffering slight attacks of rheumatism only, and at this late age was seized with abdominal pains, followed by menstruation, which continued for three years; the woman died the next year.

This late menstruation had all the sensible characters of the early one. Kennard mentions a negress, aged ninety-one, who menstruated at fourteen, ceased at forty-nine, and at eighty-two commenced again, and was regular for four years, but had had no return since. On the return of her menstruation, believing that her procreative powers were returning, she married a vigorous negro of thirty-five and experienced little difficulty in satisfying his desires.

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Du Peyrou de Cheyssiole and Bonhoure speak of an aged peasant woman, past ninety-one years of age, who menstruated regularly. Petersen describes a woman of seventy-nine, who on March 26th was seized with uterine pains lasting a few days and terminating with hemorrhagic discharge. On April 23d she was seized again, and a discharge commenced on the 25th, continuing four days. Up to the time of the report, one year after, this menstruation had been regular. There is an instance on record of a female who menstruated every three months during the period from her fiftieth to her seventy-fourth year, the discharge, however, being very slight.

Thomas cites an instance of a woman of sixty-nine who had had no menstruation since her forty-ninth year, but who commenced again the year he saw her. Her mother and sister were similarly affected at the age of sixty, in the first case attributable to grief over the death of a son, in the second ascribed to fright. It seemed to be a peculiar family idiosyncrasy. Velasquez of Tarentum says that the Abbess of Monvicaro at the very advanced age of one hundred had a recurrence of catamenia after a severe illness, and subsequently a new set of teeth and a new growth of hair.

Late Establishment of Menstruation. Perfect relates the history of a woman who had been married many years, and whose menstruation did not appear until her forty-seventh year. She was a widow at the time, and had never been pregnant. Up to the time of her death, which was occasioned by a convulsive colic, in her fifty-seventh year, she had the usual prodromes of menstruation followed by the usual discharge.

Rodsewitch speaks of a widow of a peasant who menstruated for the first time at the age of thirty-six. Her first coitus took place at the age of fifteen, before any signs of menstruation had appeared, and from this time all through her married life she was either pregnant or suckling. Her husband died when thirty-six years old, and ever since the catamenial flow had shown itself with great regularity. She had borne twins in her second, fourth, and eighth confinement, and altogether had 16 children.

Holdefrund in mentions a case in which menstruation did not commence until the seventieth year, and Hoyer mentions one delayed to the seventy-sixth year. Marx of Krakau speaks of a woman, aged forty-eight, who had never menstruated; until forty-two years old she had felt no symptoms, but at this time pain began, and at forty-eight regular menstruation ensued. At the time of report, four years after, she was free from pain and amenorrhea, and her flow was regular, though scant. She had been married since she was twenty-eight years of age. A somewhat similar case is mentioned by Gregory of a mother of 7 children who had never had her menstrual flow.

There are two instances of delayed menstruation quoted: the first, a woman of thirty, well formed, healthy, of good social position, and with all the signs of puberty except menstruation, which had never appeared; the second, a married woman of forty-two, who throughout a healthy connubial life had never menstruated. An instance is known to the authors of a woman of forty who has never menstruated, though she is of exceptional vigor and development. She has been married many years without pregnancy.

The medical literature relative to precocious impregnation is full of marvelous instances. Individually, many of the cases would be beyond credibility, but when instance after instance is reported by reliable authorities we must accept the possibility of their occurrence, even if we doubt the statements of some of the authorities. No less a medical celebrity than the illustrious Sir Astley Cooper remarks that on one occasion he saw a girl in Scotland, seven years old, whose pelvis was so fully developed that he was sure she could easily give birth to a child; and Warner's case of the Jewish girl three and a half years old, with a pelvis of normal width, more than substantiates this supposition.

Similar examples of precocious pelvic and sexual development are on record in abundance, and nearly every medical man of experience has seen cases of infantile masturbation. The ordinary period of female maturity is astonishingly late when compared with the lower animals of the same size, particularly when viewed with cases of animal precocity on record. Berthold speaks of a kid fourteen days old which was impregnated by an adult goat, and at the usual period of gestation bore a kid, which was mature but weak, to which it gave milk in abundance, and both the mother and kid grew up strong.

Compared with the above, child-bearing by women of eight is not extraordinary. The earliest case of conception that has come to the authors' notice is a quotation in one of the last century books from von Mandelslo of impregnation at six; but a careful search in the British Museum failed to confirm this statement, and, for the present, we must accept the statement as hearsay and without authority available for reference-purposes. Molitor gives an instance of precocious pregnancy in a child of eight.

It was probably the same case spoken of by Lefebvre and reported to the Belgium Academy: A girl, born in Luxemborg, well developed sexually, having hair on the pubis at birth, who menstruated at four, and at the age of eight was impregnated by a cousin of thirty-seven, who was sentenced to five years' imprisonment for seduction. The pregnancy terminated by the expulsion of a mole containing a well-characterized human embryo. Schmidt's case in was in a child who had menstruated at two, and bore a dead fetus when she was but eight years and ten months old.

She had all the appearance and development of a girl of seventeen. Kussmaul gives an example of conception at eight. Dodd speaks of a child who menstruated early and continued up to the time of impregnation. She was a hard worker and did all her mother's washing. Her labor pains did not continue over six hours, from first to the last. The child was a large one, weighing 7 pounds, and afterward died in convulsions. The infant's left foot had but 3 toes. The young mother at the time of delivery was only nine years and eight months old, and consequently must have been impregnated before the age of nine.

Meyer gives an astonishing instance of birth in a Swiss girl at nine. Carn describes a case of a child who menstruated at two, became pregnant at eight, and lived to an advanced age. Ruttel reports conception in a girl of nine, and as far north as St. Petersburg a girl has become a mother before nine years. The Journal de Scavans, , contains the report of the case of a boy, who survived, being born to a mother of nine years. Beck has reported an instance of delivery in a girl a little over ten years of age.

There are instances of fecundity at nine years recorded by Ephemerides, Wolffius, Savonarola, and others. Gleaves reports from Wytheville, Va. The girl had not the development of a woman, although she had menstruated regularly since her fifth year. The labor was short and uneventful, and, two hours afterward, the child-mother wanted to arise and dress and would have done so had she been permitted.

There were no developments of the mammae nor secretion of milk. The baby was nourished through its short existence as it only lived a week by its grandmother, who had a child only a few months old. The parents of this child were prosperous, intelligent, and worthy people, and there was no doubt of the child's age. The first case was one of infantile precocity, the other belonging to a much later period, the menstrual function having been established but a few months prior to conception. All these girls had well-developed pelves, large mammae, and the general marks of womanhood, and bore living children.

It has been remarked of 3 very markedly precocious cases of pregnancy that one was the daughter of very humble parents, one born in an almshouse, and the other raised by her mother in a house of prostitution. The only significance of this statement is the greater amount of vice and opportunity for precocious sexual intercourse to which they were exposed; doubtless similar cases under more favorable conditions would never be recognized as such.

The instance in the Journal decavans is reiterated in , which is but such a repetition as is found all through medical literature—"new friends with old faces," as it were. Haller observed a case of impregnation in a girl of nine, who had menstruated several years, and others who had become pregnant at nine, ten, and twelve years respectively.

At the time of delivery she measured 4 feet 7 inches in height and weighed pounds. Curtis, who is also quoted by Harris, relates the history of Elizabeth Drayton, who became pregnant before she was ten, and was delivered of a full-grown, living male child weighing 8 pounds. She had menstruated once or twice before conception, was fairly healthy during gestation, and had a rather lingering but natural labor. To complete the story, the father of this child was a boy of fifteen. One of the faculty of Montpellier has reported an instance at New Orleans of a young girl of eleven, who became impregnated by a youth who was not yet sixteen.

Maygrier says that he knew a girl of twelve, living in the Faubourg Saint-Germain, who was confined. Harris relates the particulars of the case of a white girl who began to menstruate at eleven years and four months, and who gave birth to an over-sized male child on January 21, , when she was twelve years and nine months old. She had an abundance of milk and nursed the child; the labor was of about eighteen hours' duration, and laceration was avoided. He also speaks of a mulatto girl, born in , who began to menstruate at eleven years and nine months, and gave birth to a female child before she reached thirteen, and bore a second child when fourteen years and seven months old.

The child's father was a white boy of seventeen. The following are some Indian statistics: 1 pregnancy at ten, 6 at eleven, 2 at eighteen, 1 at nineteen. Chevers speaks of a mother at ten and others at eleven and twelve; and Green, at Dacca, performed craniotomy upon the fetus of a girl of twelve.

Wilson gives an account of a girl thirteen years old, who gave birth to a full-grown female child after three hours' labor. She made a speedy convalescence, but the child died four weeks afterward from bad nursing. The lad who acknowledged paternity was nineteen years old. King reports a well-verified case of confinement in a girl of eleven. Both the mother and child did well. Robertson of Manchester describes a girl, working in a cotton factory, who was a mother at twelve; de La Motte mentions pregnancy before twelve; Kilpatrick in a negress, at eleven years and six months; Fox, at twelve; Hall, at twelve; Kinney, at twelve years, ten months, and sixteen days; Herrick, at thirteen years and nine months; Murillo, at thirteen years; Philippart, at fourteen years; Stallcup, at eleven years and nine months; Stoakley, at thirteen years; Walker, at the age of twelve years and eight months; another case, at twelve years and six months; and Williams, at eleven.

The consequence is that girls are married at the age of nine or ten years, but it is understood or professed that the consummation of the marriage is delayed until after the first menstrual period. There is, however, too much reason to believe that the earlier ceremony is very frequently, perhaps commonly, taken to warrant resort to sexual intercourse before the menstrual flux has occurred: it may be accepted as true that premenstrual copulation is largely practised under the cover of marriage in this country.

A native medical witness testified that in about 20 per cent of marriages children were born by wives of from twelve to thirteen years of age. Cases of death caused by the first act of sexual intercourse are by no means rare. They are naturally concealed, but ever and anon they come to light. Chevers mentioned some 14 cases of this sort in the last edition of his 'Handbook of Medical Jurisprudence for India,' and Dr. Harvey found 5 in the medicolegal returns submitted by the Civil Surgeons of the Bengal Presidency during the years This can easily be done by raising the age of punishable intercourse, which is now fixed at the absurd limit of ten years.

Menstruation very seldom appears in native girls before the completed age of twelve years, and if the 'age of consent' were raised to that limit, it would not interfere with the prejudices and customs which insist on marriage before menstruation. In some girls were admitted to the Paris Maternite as young as thirteen, and during the Revolution several at eleven, and even younger.

Smith speaks of a legal case in which a girl, eleven years old, being safely delivered of a living child, charged her uncle with rape. Allen speaks of a girl who became pregnant at twelve years and nine months, and was delivered of a healthy, 9-pound boy before the physician's arrival; the placenta came away afterward, and the mother made a speedy recovery. She was thought to have had "dropsy of the abdomen," as the parents had lost a girl of about the same age who was tapped for ascites.

The father of the child was a boy only fourteen years of age. Marvelous to relate, there are on record several cases of twins being born to a child mother. Kay reports a case of twins in a girl of thirteen; Montgomery, at fourteen; and Meigs reports the case of a young girl, of Spanish blood, at Maracaibo, who gave birth to a child before she was twelve and to twins before reaching fourteen years.

In the older works, the following authors have reported cases of pregnancy before the appearance of menstruation: Ballonius, Vogel, Morgagni, the anatomist of the kidney, Schenck, Bartholinus, Bierling, Zacchias, Charleton, Mauriceau, Ephemerides, and Fabricius Hildanus. In some cases this precocity seems to be hereditary, being transmitted from mother to daughter, bringing about an almost incredible state of affairs, in which a girl is a grandmother about the ordinary age of maternity.

Kay says that he had reported to him, on "pretty good" authority, an instance of a Damascus Jewess who became a grandmother at twenty-one years. In France they record a young grandmother of twenty-eight. Ketchum speaks of a negress, aged thirteen, who gave birth to a well-developed child which began to menstruate at ten years and nine months and at thirteen became pregnant; hence the negress was a grandmother at twenty-five years and nine months.

She had a second child before she was sixteen, who began to menstruate at seven years and six months, thus proving the inheritance of this precocity, and leaving us at sea to figure what degree of grandmother she may be if she lives to an advanced age. Another interesting case of this nature is that of Mrs. This daughter married in , and in March, , gave birth to a 9-pound boy. The youthful grandmother, not twenty-nine, was present at the birth.

This case was remarkable, as the children were both legitimate. Fecundity in the old seems to have attracted fully as much attention among the older observers as precocity. Pliny speaks of Cornelia, of the family of Serpios, who bore a son at sixty, who was named Volusius Saturnius; and Marsa, a physician of Venice, was deceived in a pregnancy in a woman of sixty, his diagnosis being "dropsy.

Among the older reports are those of Blanchard of a woman who bore a child at sixty years; Fielitz, one at sixty; Ephemerides, one at sixty-two; Rush, one at sixty; Bernstein, one at sixty years; Schoepfer, at seventy years; and, almost beyond belief, Debes cites an instance as taking place at the very advanced age of one hundred and three.

Wallace speaks of a woman in the Isle of Orkney bearing children when past the age of sixty. We would naturally expect to find the age of child-bearing prolonged in the northern countries where the age of maturity is later. Capuron cites an example of child-birth in a woman of sixty; Haller, cases at fifty-eight, sixty-three, and seventy; Dewees, at sixty-one; and Thibaut de Chauvalon, in a woman of Martinique aged ninety years.

There was a woman delivered in Germany, in , at the age of fifty-five; one at fifty-one in Kentucky; and one in Russia at fifty. Depasse speaks of a woman of fifty-nine years and five months old who was delivered of a healthy male child, which she suckled, weaning it on her sixtieth birthday. She had been a widow for twenty years, and had ceased to menstruate nearly ten years before. In St. Peter's Church, in East Oxford, is a monument bearing an inscription recording the death in child-birth of a woman sixty-two years old.

Cachot relates the case of a woman of fifty-three, who was delivered of a living child by means of the forceps, and a year after bore a second child without instrumental interference. She had no milk in her breasts at the time and no signs of secretion. This aged mother had been married at fifty-two, five years after the cessation of her menstruation, and her husband was a young man, only twenty-four years old. Kennedy reports a delivery at sixty-two years, and the Cincinnati Enquirer, January, , says: "Dr.

McCarthy was in attendance on a lady of sixty-nine years, on Thursday night last, who gave birth to a fine boy. The father of the child is seventy-four years old, and the mother and child are doing well. Henry of Gortree at the age of one hundred and twelve, leaving a daughter of nine years. Mayham saw a woman seventy-three years old who recovered after delivery of a child.

A most peculiar case is that of a widow, seventy years old, a native of Garches. She had been in the habit of indulging freely in wine, and, during the last six months, to decided excess. After an unusually prolonged libation she found herself unable to walk home; she sat down by the roadside waiting until she could proceed, and was so found by a young man who knew her and who proposed helping her home.

By the time her house was reached night was well advanced, and she invited him to stop over night; finding her more than affable, he stopped at her house over four nights, and the result of his visits was an ensuing pregnancy for Madame. Multiple births in the aged have been reported from authentic sources. The Lancet quotes a rather fabulous account of a lady over sixty-two years of age who gave birth to triplets, making her total number of children Montgomery, Colomb, and Knehel, each, have recorded the birth of twins in women beyond the usual age of the menopause, and there is a case recorded of a woman of fifty-two who was delivered of twins.

Impregnation without completion of the copulative act by reason of some malformation, such as occlusion of the vagina or uterus, fibrous and unruptured hymen, etc. There is little doubt of the possibility of spermatozoa deposited on the genitalia making progress to the seat of fertilization, as their power of motility and tenacity of life have been well demonstrated. Percy reports an instance in which semen was found issuing from the os uteri eight and one-half days after the last intercourse; and a microscopic examination of this semen revealed the presence of living as well as dead spermatozoa.

We have occasional instances of impregnation by rectal coitus, the semen finding its way into an occluded vaginal canal by a fistulous communication. Guillemeau, the surgeon of the French king, tells of a girl of eighteen, who was brought before the French officials in Paris, in , on the citation of her husband of her inability to allow him completion of the marital function.

He alleged that he had made several unsuccessful attempts to enter her, and in doing so had caused paraphimosis. On examination by the surgeons she was found to have a dense membrane, of a fibrous nature, entirely occluding the vagina, which they incised. Immediately afterward the woman exhibited morning sickness and the usual signs of pregnancy, and was delivered in four months of a full-term child, the results of an impregnation occasioned by one of the unsuccessful attempts at entrance. Such instances are numerous in the older literature, and a mere citation of a few is considered sufficient here.

Zacchias, Amand, Fabricius Hildanus, Graaf, the discoverer of the follicles that bear his name, Borellus, Blegny, Blanchard, Diemerbroeck, Duddell, Mauriceau, a Reyes, Riolan, Harvey, the discoverer of the circulation of the blood, Wolfius, Walther, Rongier, Ruysch, Forestus, Ephemerides, and Schurig all mention cases of conception with intact hymen, and in which there was no entrance of the penis. Tolberg has an example of hymen integrum after the birth of a fetus five months old, and there is recorded a case of tubal pregnancy in which the hymen was intact.

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Gilbert gives an account of a case of pregnancy in an unmarried woman, who successfully resisted an attempt at criminal connection and yet became impregnated and gave birth to a perfectly formed female child. The hymen was not ruptured, and the impregnation could not have preceded the birth more than thirty-six weeks.

Unfortunately, this poor woman was infected with gonorrhea after the attempted assault. Simmons of St. Louis gives a curious peculiarity of conception, in which there was complete closure of the vagina, subsequent conception, and delivery at term. He made the patient's acquaintance from her application to him in regard to a malcondition of her sexual apparatus, causing much domestic infelicity. Lawson speaks of a woman of thirty-five, who had been married ten months, and whose husband could never effect an entrance; yet she became pregnant and had a normal labor, despite the fact that, in addition to a tough and unruptured hymen, she had an occluding vaginal cyst.

Hickinbotham of Birmingham reports the history of two cases of labor at term in females whose hymens were immensely thickened. Grey Edwards has seen a case of imperforate hymen which had to be torn through in labor; yet one single act of copulation, even with this obstacle to entrance, sufficed to impregnate. Champion speaks of a woman who became pregnant although her hymen was intact. She had been in the habit of having coitus by the urethra, and all through her pregnancy continued this practice.

Houghton speaks of a girl of twenty-five into whose vagina it was impossible to pass the tip of the first finger on account of the dense cicatricial membrane in the orifice, but who gave birth, with comparative ease, to a child at full term, the only interference necessary being a few slight incisions to permit the passage of the head. Tweedie saw an Irish girl of twenty-three, with an imperforate os uteri, who had menstruated only scantily since fourteen and not since her marriage. She became pregnant and went to term, and required some operative interference.

He incised at the point of usual location of the os, and one of his incisions was followed by the flow of liquor amnii, and the head fell upon the artificial opening, the diameter of which proved to be one and a half or two inches; the birth then progressed promptly, the child being born alive. Guerard notes an instance in which the opening barely admitted a hair; yet the patient reached the third month of pregnancy, at which time she induced abortion in a manner that could not be ascertained.

Roe gives a case of conception in an imperforate uterus, and Duncan relates the history of a case of pregnancy in an unruptured hymen, characterized by an extraordinary ascent of the uterus. Among many, the following modern observers have also reported instances of pregnancy with hymen integrum: Braun, 3 cases; Francis, Horton, Oakman, Brill, 2 cases; Burgess, Haig, Hay, and Smith.

Instances in which the presence of an unruptured hymen has complicated or retarded actual labor are quite common, and until the membrane is ruptured by external means the labor is often effectually obstructed. There are many cases of stricture or complete occlusion of the vagina, congenital or acquired from cicatricial contraction, obstructing delivery, and in some the impregnation seems more marvelous than cases in which the obstruction is only a thin membranous hymen.

Often the obstruction is so dense as to require a large bistoury to divide it, and even that is not always sufficient, and the Cesarean operation only can terminate the obstructed delivery; we cannot surmise how conception could have been possible. Staples records a case of pregnancy and parturition with congenital stricture of the vagina. Maisonneuve mentions the successful practice of a Cesarean operation in a case of congenital occlusion of the vagina forming a complete obstruction to delivery.

Verdile records an instance of imperforate vagina in which rectovaginal wall was divided and the delivery effected through the rectum and anus. Lombard mentions an observation of complete occlusion of the vagina in a woman, the mother of 4 living children and pregnant for the fifth time. Thus, almost incredible to relate, it is possible for a woman to become a mother of a living child and yet preserve all the vaginal evidences of virginity. Cole describes a woman of twenty-four who was delivered without the rupture of the hymen, and Meek remarks on a similar case. We can readily see that, in a case like that of Verdile, in which rectal delivery is effected, the hymen could be left intact and the product of conception be born alive.

A natural sequence to the subject of impregnation without entrance is that of artificial impregnation. From being a matter of wonder and hearsay, it has been demonstrated as a practical and useful method in those cases in which, by reason of some unfortunate anatomic malformation on either the male or the female side, the marriage is unfruitful. There are many cases constantly occurring in which the birth of an heir is a most desirable thing in a person's life.

The historic instance of Queen Mary of England, whose anxiety and efforts to bear a child were the subject of public comment and prayers, is but an example of a fact that is occurring every day, and doubtless some of these cases could be righted by the pursuance of some of the methods suggested. There have been rumors from the beginning of the century of women being impregnated in a bath, from contact with cloths containing semen, etc.

It is not in the province of this work to speculate on what may be, but to give authoritative facts, from which the reader may draw his own deductions. Fertilization of plants has been thought to have been known in the oldest times, and there are some who believe that the library at Alexandria must have contained some information relative to it. The first authentic account that we have of artificial impregnation is that of Schwammerdam, who in attempted it without success by the fecundation of the eggs of fish.

Roesel, his scholar, made an attempt in , but also failed; and to Jacobi, in , belongs the honor of success. In , Abbe Spallanzani, following up the success of Jacobi, artificially impregnated a bitch, who brought forth in sixty-two days 3 puppies, all resembling the male. The illustrious John Hunter advised a man afflicted with hypospadias to impregnate his wife by vaginal injections of semen in water with an ordinary syringe, and, in spite of the simplicity of this method, the attempt was followed by a successful issue.

Since this time, Nicholas of Nancy and Lesueur have practised the simple vaginal method; while Gigon, d'Angouleme 14 cases , Girault 10 cases , Marion Sims, Thomas, Salmon, Pajot, Gallard, Courty, Roubaud, Dehaut, and others have used the more modern uterine method with success. A dog-breeder, by syringing the uterus of a bitch, has succeeded in impregnating her. Those who are desirous of full information on this subject, as regards the modus operandi, etc. One case was that of a woman, aged twenty-five, afflicted with blenorrhea, who, chagrined at not having issue, made repeated forcible injections of semen in water for two months, and finally succeeded in impregnating herself, and was delivered of a living child.

Another case was that of a female, aged twenty-three, who had an extra long vaginal canal, probably accounting for the absence of pregnancy. She made injections of semen, and was finally delivered of a child. He also reports the case of a distinguished musician who, by reason of hypospadias, had never impregnated his wife, and had resorted to injections of semen with a favorable result.

This latter case seems hardly warranted when we consider that men afflicted with hypospadias and epispadias have become fathers. Percy gives the instance of a gentleman whom he had known for some time, whose urethra terminated a little below the frenum, as in other persons, but whose glans bulged quite prominently beyond it, rendering urination in the forward direction impossible.

Despite the fact that this man could not perform the ejaculatory function, he was the father of three children, two of them inheriting his penile formation. The fundamental condition of fecundity being the union of a spermatozoid and an ovum, the object of artificial impregnation is to further this union by introducing semen directly to the fundus of the uterus. The operation is quite simple and as follows: The husband, having been found perfectly healthy, is directed to cohabit with his wife, using a condom.

The semen ejaculated is sucked up by an intrauterine syringe which has been properly disinfected and kept warm. The os uteri is now exposed and wiped off with some cotton which has been dipped in an antiseptic fluid; introduced to the fundus of the uterus, and some drops of the fluid slowly expressed into the uterus. The woman is then kept in bed on her back. This operation is best carried out immediately before or immediately after the menstrual epoch, and if not successful at the first attempt should be repeated for several months. At the present day artificial impregnation in pisciculture is extensively used with great success.

Capers of Vicksburg, Miss. During the fray a gallant and noble young friend of the narrator staggered and fell to the earth; at the same time a piercing cry was heard in the house near by. Examination of the wounded soldier showed that a bullet had passed through the scrotum and carried away the left testicle.

The same bullet had apparently penetrated the left side of the abdomen of the elder young lady, midway between the umbilicus and the anterior superior spinous process of the ilium, and had become lost in the abdomen. This daughter suffered an attack of peritonitis, but recovered in two months under the treatment administered. Marvelous to relate, just two hundred and seventy-eight days after the reception of the minie-ball, she was delivered of a fine boy, weighing 8 pounds, to the surprise of herself and the mortification of her parents and friends.

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