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PubMed1978

[Somatic disorders and depressive states].

Somatic disorders in depression can be separated into two main categories. The first comprises those which are true side effets of drug-therapy; the other includes somatic symptoms of the depression itself, which are subsequently considered as apparent side effects. Under the same treatment true side effects occur much more frequently in psychogenic depression, especially if the patient has a personality disorder. During the course of the treatment the disappearance of somatic complaints is noticed more easily by the physicians than the appearance of true side effects (schulterbrandt). The relative frequency of symptoms of depression as compared with all other symptoms seems to be higher in manic-depressive psychoses than in other varieties of depression (Watts). The other somatic disorders might either be symptoms of organic illness with secondary depression, the psycho-somatic equivalents of depression, or finaly the only symptoms of a masked depression.

Amitriptyline↗
PubMed1995

Somatic mutations of the adenomatous polyposis coli gene in gastroduodenal tumors from patients with familial adenomatous polyposis.

We analyzed somatic mutations of the adenomatous polyposis coli (APC), p53, and K-ras genes in gastroduodenal polyps and normal gastroduodenal mucosa from 21 familial adenomatous polyposis patients, using PCR-single-strand conformation polymorphism and direct sequencing methods. Seventy-five polyps were obtained from these patients endoscopically or surgically, and they were histopathologically diagnosed as mild adenoma, moderate adenoma, severe adenoma, adenocarcinoma, and fundic gland polyp. Examining the APC-coding region where somatic mutations in colorectal tumors are known to be clustered, we detected 47 somatic mutations. The frequency of mutation detected was 6 of 9 (67%) in ampullary adenomas, 1 of 2 (50%) in ampullary adenocarcinoma, 11 of 24 (46%) in non-ampullary adenomas, 26 of 29 (90%) in gastric adenomas, and 3 of 11 (27%) in gastric fundic gland polyps. These mutations frequently occurred at codons 1450, 1462-1465, and 1554-1556, the third being a newly found hot spot. All mutations formed stop codons that resulted in truncated APC proteins. K-ras mutation was detected only in an ampullary adenocarcinoma, and p53 mutation was not detected in any of the tumors analyzed. There was no somatic mutation detected in samples of flat mucosa that were diagnosed as normal mucosa both endoscopically and histopathologically. Frequent APC mutations in mild and small adenomas, similar to the findings in severe and large adenomas, suggested that the genetic change in the APC gene occurs in an early stage of forming gastroduodenal adenomas. Moreover, the presence of somatic APC mutations in fundic gland polyps suggests that inactivation of the APC gene plays a role not only in forming adenomas but also in forming hyperplastic polyps in fundic gland mucosa, and there may be some additional steps to the adenoma-carcinoma sequence.

Adenomatous Polyposis Coli↗
PubMed1995

Pharmacological analysis of the noradrenergic control of central sympathetic and somatic reflexes controlling the lower urinary tract in the anesthetized cat.

Norepinephrine (NE)-containing terminals densely innervate sympathetic preganglionic neurons in the intermediolateral nucleus and somatic motor neurons in Onuf's nucleus that project through the hypogastric and pudendal nerves, respectively, to innervate the lower urinary tract. In the present study, we pharmacologically analyzed the role of noradrenergic systems on the sympathetic and somatic pathways to the lower urinary tract and asked: 1) Are alpha-1, alpha-2, or beta-adrenergic receptors tonically active along sympathetic and/or somatic reflex pathways? And 2) what is the net effect of increasing the extracellular levels of NE by administration of a NE reuptake inhibitor? To address these questions, we recorded evoked potentials from the central ends of the hypogastric and pudendal nerves in response to electrical stimulation of the pelvic and pudendal nerves in chloralose-anesthetized cats, and the effects of prazosin (1-300 micrograms/kg i.v.), an alpha-1-adrenergic receptor antagonist; idazoxan (1-300 micrograms/kg i.v.), an alpha-2-adrenergic receptor antagonist; propranolol (1 mg/kg i.v.), a beta-adrenergic receptor antagonist; and tomoxetine (0.003-3 mg/kg i.v.), a selective NE reuptake inhibitor, were examined. The results indicate that facilitatory alpha-1-adrenergic receptors are tonically active along both sympathetic and somatic reflex pathways, whereas inhibitory alpha-2-adrenergic receptors are not tonically active. The net effect of acute inhibition of NE reuptake along sympathetic reflex pathways is increased activation of inhibitory alpha-2-adrenergic receptors. Along somatic reflex pathways, increased activation of both facilitatory alpha-1- and inhibitory alpha-2-adrenergic receptors were recorded after acute NE reuptake inhibition. No role for central beta-adrenergic receptors was noted.

Anesthesia↗
PubMed1995

Somatic mutations of PIG-A in Thai patients with paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a hematopoietic stem cell disorder characterized by clonal blood cells that are deficient in the surface expression of glycosylphosphatidylinositol (GPI)-anchored proteins. In the affected cells, the X-chromosomal gene PIG-A, which participates in biosynthesis of the GPI anchor, is somatically mutated. Analyses of Japanese, British, and American patients with PNH have shown somatic mutations of PIG-A in all of them, indicating that PIG-A is responsible for PNH in most, if not all, patients in those countries. Twenty-nine of the reported somatic mutations are small, mostly involving 1 or 2 bases, except for one with a 4-kb deletion. Here we describe an analysis of PIG-A in neutrophils from 14 patients from Thailand where PNH is thought to be more common. We found small somatic PIG-A mutations in all patients. These consisted of six single base deletions, one each of 2-, 3-, 5- and 10-base deletions, two single base insertions and two base substitutions. Thus, the small somatic mutation in the PIG-A gene is also responsible for PNH in Thailand. However, base substitutions were rarer (2 of 14) than in Japan (8 of 16), and deletions of multiple bases were more common, suggesting various causes of mutation.

Base Sequence↗
PubMed1976

[Somatic polyploidy in animal embryogenesis].

The evidence provided in our laboratory on somatic polyploidy is reviewed. The development of some embryonal cell populations being taken as an example, the main problems of somatic polyploidy are discussed: somatic polyploidy and proliferation, growth, cell differentiation and specialization, the significance of polyploidy in the development of embryonal populations, in the realization of development programs etc. The term "somatic polyploidy" is not thought to involve the complex of phenomena it designates. A new, more precise and general concept is proposed--"hyperreplication of DNA", which seems to cover indeed the whole complex of phenomena characterizing the increase of DNA content in the nuclei of somatic cells including the polyploid ones.

Animals↗
PubMed1994

Variation of somatic cell counts in colostrum and milk of first and second lactation cows during ten days after calving.

Samples of mammary gland secretions were collected during the first 10 post partum days from six 1st lactations and six 2nd lactation Holstein-Friesian cows. Mean (+/- SD) somatic cell counts in quarter foremilk samples were 447 (+/- 241). 10(3)/ml and 620 (+/- 246). 10(3)/ml in the 1st and 2nd lactation cows, respectively. The difference was significant (P < 0.05). The corresponding values for bucket milk samples were 355 (+/- 320). 10(3)/ml and 517 (+/- 242) 10(3)/ml, respectively. The difference was insignificant (P > 0.05). Mean foremilk somatic cell counts were significantly higher than mean bucket milk counts in both the 1st and the 2nd lactation cows (P < 0.05 and P < 0.01 respectively). A negative correlation between somatic cell counts in both foremilk and bucket milk samples and milk yield was evident in both groups of cows. Somatic cell counts decreased rapidly in bucket milk samples and were lower than 261.10(3)/ml and 192.10(3)/ml in the 1st and the 2nd lactation cows, respectively, on post partum day 10. Values higher than 300.10(3) cells/ml were not found in any of bucket milk samples collected on post partum day 5. Higher counts were found only in foremilk quarter samples collected from 2 glands of 1st lactation and 1 gland of a 2nd lactation cow. None of the mammary glands of any of the cows became infected during the investigation period. Somatic cell counts in non-infected 1st and 2nd lactation cows are apparently time-dependent and cannot be regarded as characteristic features of individual animals.

Animals↗
PubMed1995

Burkitt's lymphoma is a malignancy of mature B cells expressing somatically mutated V region genes.

BACKGROUND: The developmental stage from which stems the malignant B cell population in Burkitt's lymphoma (BL) is unclear. An approach to answering this question is provided by the sequence analysis of rear-ranged immunoglobulin (Ig) variable region (V) genes from BL for evidence of somatic mutations, together with a phenotypic characterization. As somatic hypermutation of Ig V region genes occurs in germinal center B cells, somatically mutated Ig genes are found in germinal center B cells and their descendents. MATERIALS AND METHODS: Rearranged V kappa region genes from 10 kappa-expressing sporadic and endemic BL-derived cell lines (9 IgM and 1 IgG positive) and three kappa-expressing endemic BL biopsy specimens were amplified by polymerase chain reaction and sequenced. In addition, VH region gene sequences from these cell lines were determined. RESULTS: All BL cell lines and the three biopsy specimens carried somatically mutated V region genes. The average mutation frequency of rearranged V kappa genes from eight BL cell lines established from sporadic BL was 1.8%. A higher frequency (6%) was found in five endemic cases (three biopsy specimens and two BL cell lines). CONCLUSIONS: The detection of somatic mutations in the rearranged V region genes suggests that both sporadic and endemic BL represent a B-cell malignancy originating from germinal center B cells or their descendants. Interestingly, the mutation frequency detected in sporadic BL is in a range similar to that characteristic for IgM-expressing B cells in the human peripheral blood and for mu chain-expressing germinal center B cells, whereas the mutation frequency found in endemic BL is significantly higher.

B-Lymphocytes↗
PubMed1996

Somatically mutated B cell pool provides precursors for insulin antibodies.

Antibodies to insulin are products of autoreactive B lymphocytes that escape inactivation or clonal deletion and are examples of "clonal ignorance." To understand the genetic origin of Abs from clonally ignorant B cells, the roles of somatic mutation and germ-line V(H) structures were examined for two murine IgG1 mAb that bind human and rodent insulin. Engineered mAb constructs that express germ-line or mutated V(H) genes show that somatic mutations introducing aspartic acid in or adjacent to CDRH2 play a key role in insulin binding. When either of the two anti-insulin V(H) regions is returned to its germ-line (unmutated) sequence, neither mAb binds insulin and the germ-line-encoded mAb are not polyreactive. Reconstruction of the somatic evolution of insulin binding in both mAbs shows that a single mutation in CDRH2 is sufficient to generate anti-insulin activity from a nonbinding precursor. When the role of somatic mutation in the binding of rodent insulin is examined, autoreactivity is associated with single mutations in both Abs. Together these findings indicate that, despite a low mutation frequency, IgG insulin Abs may not be derived directly from germ-line (unmutated) precursors. The requirement for somatic mutation as a prerequisite for measurable insulin binding suggests these Abs have their origin in a previously mutated B cell pool as a consequence of the individual's immune history. Low avidity interaction with endogenous insulin may play a role in selection of these B cells and contribute to the origin of clonal ignorance.

Amino Acid Sequence↗
PubMed1996

Remodeling somatic nuclei in Xenopus laevis egg extracts: molecular mechanisms for the selective release of histones H1 and H1(0) from chromatin and the acquisition of transcriptional competence.

The molecular mechanisms responsible for the remodeling of entire somatic erythrocyte nuclei in Xenopus laevis egg cytoplasm have been examined. These transitions in chromosomal composition are associated with the capacity to activate new patterns of gene expression and the re-acquisition of replication competence. Somatic linker histone variants H1 and H1 (0) are released from chromatin in egg cytoplasm, whereas the oocyte-specific linker histone B4 and HMG1 are efficiently incorporated into remodeled chromatin. Histone H1 (0) is released from chromatin preferentially in comparison with histone H1. Core histones H2A and H4 in the somatic nucleus are phosphorylated during this remodeling process. These transitions recapitulate the chromosomal environment found within the nuclei of the early Xenopus embryo. Phosphorylation of somatic linker histone variants is demonstrated not to direct their release from chromatin, nor does direct competition with cytoplasmic stores of linker histone B4 determine their release. However, the molecular chaperone nucleoplasmin does have an important role in the selective removal of linker histones from somatic nuclei. For Xenopus erythrocyte nuclei, this disruption of chromatin structure leads to activation of the 5S rRNA genes. These results provide a molecular explanation for the remodeling of chromatin in Xenopus egg cytoplasm and indicate the capacity of molecular chaperones to disrupt a natural chromosomal environment, thereby facilitating transcription.

Animals↗
PubMed1996

Identification of somatic hybrids between rice cultivar and wild Oryza species by RAPD.

The somatic hybrids between rice cultivar and wild Oryza species were obtained by the PEG and electrical fusion method. The somatic hybrids were identified with PAPD. It was verified that the genome of somatic hybrids contained some genomes from both parents, but they contributed unequally. In some somatic hybrids, the portion from one parent was more than the other. The relationship between somatic hybrids and their parents was analyzed based on RAPD data.

DNA↗
PubMed1997

[Consultation-liaison-psychiatry in Norway. Use of psychiatric services in somatic departmetns].

The aim of the present study was to assess the use of consultation-liaison psychiatry in Norway, the resources used, the organisation and quality of the services, and whether there is a need to increase the services and improve the education. A questionnaire was mailed to all the major somatic and psychiatric departments in Norway. The questionnaires were completed and returned by 189 somatic departments (85%) and 74 psychiatric departments (55%). Each psychiatric department gives a median of two consultations each week (range 1-13). A minority of the consultations are with a specialist in psychiatry. About 60% of the psychiatric departments offer supervision of younger doctors. Psychiatric evaluation is seldom carried out when the somatic diagnosis is unclear. Most of the somatic departments are satisfied with the services. Both the somatic and psychiatric departments express a need for more extensive services and more education in medical psychology.

Clinical Competence↗
PubMed1997

In vitro triggering of somatic mutation in human naive B cells.

During T cell-dependent immune response, germinal center B cells accumulate somatic mutations in their Ig V(D)J genes and give rise to affinity-selected B cells. We tested several culture conditions for triggering somatic mutation in human tonsillar naive slgD+CD23+ cells after cross-linking their membrane Igs. CD40 activation, in the presence of exogenous cytokines (IL-2, IL-4, and IL-10), induced proliferation and isotype switch without somatic mutation. In contrast, after coculture with anti-CD3-activated cloned T cells, somatic mutation accumulated in a fraction of naive B cells. Mutations included shared as well as independent events in clonally related sequences, allowing reconstitution of genealogic trees generated in vitro. Naive tonsillar B cells sorted for slgD expression can be induced to mutate their Ig V(H) gene upon coculture with activated T cells, thereby providing a model to study somatic hypermutation in vitro.

Amino Acid Sequence↗
PubMed1997

Hypochondriacal concerns and somatization in panic disorder.

To clarify the relationship between panic disorder and the symptoms of hypochondriasis and somatization, we evaluated these symptoms and diagnoses in patients attending an Anxiety Disorders Clinic. Structured clinical interviews, self-report measures, and symptom diaries were used to assess 21 patients with panic disorder, 23 patients with social phobia, and 22 control subjects with no psychiatric disorders. Ten of the patients with panic disorder (48%) also met DSM-IV criteria for hypochondriasis, whereas only one of the patients with social phobia and none of the healthy control subjects met the criteria for this diagnosis. None of the participants met DSM-IV criteria for somatization disorder, even though both anxiety groups reported high levels of somatic symptoms. The panic disorder group reported higher levels of fear about illness and disease conviction and endorsed more somatic symptoms than did the other groups. A higher proportion of panic disorder patients reported previously diagnosed medical conditions (48%) as compared with patients with social phobia (17%) or healthy control subjects (14%). The panic disorder patients with DSM-IV hypochondriasis obtained higher scores on measures of hypochondriacal concerns, somatization, blood-injury phobia, and general anxiety and distress than did the panic disorder patients without hypochondriasis. The results suggest a strong association between panic disorder and hypochondriasis.

Adult↗
PubMed1998

Somatic instability of the APC I1307K allele in colorectal neoplasia.

The adenomatous polyposis coli (APC) gene is proposed to function as a gatekeeper of colorectal neoplasia. A germ-line variant of this gene, the APC I1307K allele, is present in approximately 6% of the Ashkenazi Jewish population. To assess the role in tumorigenesis of the variant (A)8 tract produced by this allele, we undertook a somatic mutation analysis of the region surrounding codon 1307 in colorectal tumors from APC I1307K carriers. Somatic mutations involving the variant (A)8 tract were identified in 53 of 127 (42%) tumors from APC I1307K carriers compared with 5 of 127 (4%) mutations involving the wild-type allele of these tumors (P < 0.0001). Loss of heterozygosity of the wild-type allele was significantly more common in tumors with APC I1307K allele mutations (25 of 41, 61%) compared with APC I1307K carrier tumors without mutation of the variant (A)8 tract (12 of 53, 23%; P < 0.0005). This somatic biallelic APC inactivation further confirms the biological importance of the I1307K germ-line variant. The vast majority of APC I1307K somatic mutations consisted of a single adenine insertion (insA) involving the variant (A)8 tract. This insA mutation was mutually exclusive of the presence of microsatellite instability with 0 of 49 tumors with insA displaying BAT-26 instability compared with 9 of 78 tumors without insA (P=0.01). These findings support a model where somatic instability of the (A)8 tract produced by the APC I1307K allele leads to increased APC gene inactivation and directly accounts for 42% of the colorectal neoplasms occurring in APC I1307K carriers.

Adenomatous Polyposis Coli↗
PubMed1999

Two alternatively spliced Meig1 messenger RNA species are differentially expressed in the somatic and in the germ-cell compartments of the testis.

Previous studies regarding the transcriptional pattern of the murine Meig1 gene (formally designated meg1) suggested that its transcription is restricted to germ cells at the first meiotic prophase, in both primary spermatocytes and primary oocytes. However, protein analysis revealed that certain forms of the MEIG1 protein exist in testes of early postnatal pups at stages that have no germ cells in the testis, excluding very few primitive type A spermatogonia cells. This suggested that MEIG1 expression is not confined to germ cells. In this study, we show that testicular somatic cells do, indeed, express MEIG1. This is especially evident in Leydig cells, where this protein is highly abundant. We also demonstrate that alternatively spliced mRNAs of Meig1 are differentially transcribed in the germ cell and the somatic compartments of the testis. There is a very low level of somatic transcript, whether labile or transcriptionally regulated, in contrast to the abundant MEIG1 protein in the somatic cells. This implies that the somatic transcript is very efficiently translated and reconfirms that protein levels do not necessarily reflect transcript abundancy. Structural features of the Meig1 transcript that would be expected to inhibit translation are discussed in light of the efficient translation of this RNA species.

Alternative Splicing↗
PubMed1999

Functional characterization of the somatic hypermutation process leading to antibody D1.3, a high affinity antibody directed against lysozyme.

The impact of somatic hypermutation on the affinity of Abs directed against protein Ags remains poorly understood. We chose as a model the secondary response Ab D1.3 directed against hen egg lysozyme. During the maturation process leading to this Ab, five replacement somatic mutations occurred. After reconstituting the germline Ab from which D1.3 originated, we assessed the energetic and kinetic importance of each of the somatic mutations, individually or combined, using the BIAcore apparatus. We found that the mutations induced an overall 60-fold improvement of affinity, principally due to a decrease in the kinetic rate of dissociation. We showed that their effects were additive and context independent; therefore, in the case of D1.3, the order in which somatic mutations were introduced and selected is unimportant. Interestingly, most of the affinity improvement was due to a single somatic mutation (Asn50-->Tyr in VL), involving a residue that belongs to the functional interface between Ab D1.3 and lysozyme. This replacement could either establish new Van der Waals contacts between the Ab and the Ag or help stabilize the conformation of a closely situated crucial residue of the Ab paratope. The four other mutations played only a marginal part in affinity maturation; potential reasons for which these mutations were nevertheless selected are discussed.

Animals↗
PubMed2001

Analysis of antibodies of known structure suggests a lack of correspondence between the residues in contact with the antigen and those modified by somatic hypermutation.

Forty unique murine antibody-antigen complexes determined at 2.5 A or less resolution are analyzed to determine whether the residues in direct contact with the antigen are modified by somatic hypermutation. This was done by taking advantage of the recent characterization of the pool of Vkappa germline genes of the mouse. The average number of residues in contact with the antigen in the V(L) gene, which contains the CDRL-1, CDRL-2, and all but one residue of CDRL-3, was six. The average number of somatic mutations was similar (around five). However, as many as 53% of the antibodies did not show somatic replacements of residues in contact with the antigen. Another 28% had only one. Overall, the frequency of antibodies with increasing number of somatic replacements in residues in contact with the antigen decreased exponentially. A possible explanation of this finding is that mutations in the contacting residues have an adverse effect on the antigen-antibody interaction. This implies that most of the observed mutations are those remaining after negative (purifying) selection. Therefore, efficient strategies of site-directed mutagenesis to improve the affinity of antibodies should be focused on residues other than those directly interacting with the antigen.

Animals↗
PubMed2002

Somatic hypermutation and V(H) gene usage in mantle cell lymphoma.

Mantle cell lymphoma (MCL) is considered to derive from naïve, pregerminal center (GC) CD5+ B-cells. However, the cell of origin has been questioned in recent studies that showed somatic hypermutations in the immunoglobulin (Ig) variable heavy chain (V(H)) genes in subsets of MCL. To clarify this issue, we analyzed the IgV(H) genes for the presence of somatic hypermutations in 51 MCL cases. Twenty percent of the MCL cases displayed somatically mutated V(H) genes (defined as >2% mutated), whereas 80% showed unmutated V(H) genes. This finding suggests that MCL is a genetically heterogeneous disease, with the majority of cases originating from unmutated pre-GC B-cells and a subset deriving from more mature B-cells which have been exposed to the GC environment and have undergone somatic hypermutation. A biased V(H) gene usage has been demonstrated in several B-cell malignancies; however, this has not yet been investigated in MCL, although V(H)4-34 overusage has been indicated by small studies. Interestingly, we found a restricted usage of three individual V(H) genes in our MCL material; V(H)4-34 (22%), V(H)3-21 (16%) and V(H)5-51 (12%). This novel finding of preferential V(H) gene usage in half of the MCL cases may suggest an antigen driven process occurring in B-cells expressing specific VH genes, thus implicating that Ig specificity could be involved in mantle cell lymphoma development.

Adult↗