Abnormalities In Multiple Systems Research Articles

B-cell function in chronic heart failure: Antibody response to pneumococcal vaccine

Background: Several immune system abnormalities have been noted in patients with chronic heart failure (CHF) including autoantibody production and abnormalities in tumor necrosis factor, interleukin 2, interleukin 6, natural killer cells, helper/inducer lymphocytes, lymphocyte reactivity, and subtherapeutic responses to the influenza vaccination. Patients with CHF have a higher risk of nosocomial infections, mainly pulmonary. Immune function abnormalities in patients with CHF raise concern over the ability of patients with symptomatic CHF to mount an effective and protective B-cell response. Methods and Results: B-cell function was assessed by measuring antibody production in response to pneumococcal vaccination. Antibody levels were increased markedly for all serotypes tested (P ≤.001), and all patients had an increase in the number of serotypes for which they had protective antibody levels from a mean of 7.9 to 10.5 of 12 serotypes tested (P ≤.001). These responses are consistent with normal responses to vaccination. Conclusions: Despite evidence of multiple immune system abnormalities, patients with CHF seem to have an intact B-cell function and the etiology of CHF does not affect antibody response. The normal response to vaccination confirms the potential utility of the vaccination.

Valproic acid embryopathy: Report of two siblings with further expansion of the phenotypic abnormalities and a review of the literature

Fetal Valproate Syndrome (FVS) results from prenatal exposure to valproic acid (VPA). It is characterized by a distinctive facial appearance, a cluster of minor and major anomalies, and central nervous system dysfunction. In this study, two siblings who were exposed to monotherapy with VPA are described with documentation of long-term follow up. Both children had craniofacial findings, multiple systemic and orthopedic abnormalities, an overgrowth pattern, and developmental deficits. The literature from 1978–2000 is reviewed. A total of 69 cases that were solely exposed to VPA with adequate phenotypic description were identified. The clinical manifestations of FVS encompass a wide spectrum of abnormalities including consistent facial phenotype, multiple systemic and orthopedic involvement, central nervous system dysfunction, and altered physical growth. The facial appearance is characterized by a small broad nose, small ears, flat philtrum, a long upper lip with shallow philtrum, and micro/retrognathia. In this review, 62% of the patients had musculoskeletal abnormalities, 30% had minor skin defects, 26% had cardiovascular abnormalities, 22% had genital abnormalities, and 16% had pulmonary abnormalities. Less frequently encountered abnormalities included brain, eye, kidney, and hearing defects. Neural tube defects were seen in 3% of the sample. Twelve percent of affected children died in infancy and 29% of surviving patients had developmental deficits/mental retardation. Although 15% of patients had growth retardation, an overgrowth pattern was seen in 9%. The data from this comprehensive review especially the developmental outcome should be added to the teratogenic risk, that arises in association with the use of VPA during pregnancy. © 2001 Wiley-Liss, Inc.

Lead-related effects on rat fibroblasts.

Lead (Pb) is an environmental toxicant that can induce structural and functional abnormalities of multiple organ systems, including the central nervous and the immune systems. The aim of this study was to evaluate the effects of extracellular Pb supplementation on the cellular content of the metal and on the proliferation and the survival of normal rat fibroblasts. We found that the concentration of Pb in the culture medium was 0.060 microM and the normal Pb concentration in rat fibroblasts was 3.1 +/- 0.1 ng/10(7) cells. Then we exposed the cells to increasing concentration of Pb (as Pb acetate) from 0.078-320 microM. We observed a dose-dependent inhibition of cell proliferation after 48 h, which was already apparent at a concentration of 0.312 microM (p = 0.122) and became statistically significant for concentration higher than 0.625 microM (p = 0.0003 at 5 microM). Cell proliferation was completely compromised at 320 microM Pb total inhibition of cell proliferation. To investigate the mechanisms of Pb-mediated inhibition of cell proliferation, we evaluated the occurrence of apoptosis in the same cells and found that cytosolic DNA fragments, hallmark of apoptotic cell death, increased significantly at Pb concentrations from 2.5-10.0 microM. The occurrence of apoptosis was also confirmed by FACS analysis which showed the appearance of a subdiploid peak at Pb concentrations from 5-20 microM. The distribution of cells in the cell cycle showed a dose-dependent accumulation of cells in the G0/G1 phase mainly compensated by a decrease in the percentage of cells in the S phase. In conclusion, our results demonstrate that induction of apoptosis contributes to the Pb-induced inhibition of cell proliferation in rat fibroblasts.

Valproic acid embryopathy: Report of two siblings with further expansion of the phenotypic abnormalities and a review of the literature

Fetal Valproate Syndrome (FVS) results from prenatal exposure to valproic acid (VPA). It is characterized by a distinctive facial appearance, a cluster of minor and major anomalies, and central nervous system dysfunction. In this study, two siblings who were exposed to monotherapy with VPA are described with documentation of long-term follow up. Both children had craniofacial findings, multiple systemic and orthopedic abnormalities, an overgrowth pattern, and developmental deficits. The literature from 1978-2000 is reviewed. A total of 69 cases that were solely exposed to VPA with adequate phenotypic description were identified. The clinical manifestations of FVS encompass a wide spectrum of abnormalities including consistent facial phenotype, multiple systemic and orthopedic involvement, central nervous system dysfunction, and altered physical growth. The facial appearance is characterized by a small broad nose, small ears, flat philtrum, a long upper lip with shallow philtrum, and micro/retrognathia. In this review, 62% of the patients had musculoskeletal abnormalities, 30% had minor skin defects, 26% had cardiovascular abnormalities, 22% had genital abnormalities, and 16% had pulmonary abnormalities. Less frequently encountered abnormalities included brain, eye, kidney, and hearing defects. Neural tube defects were seen in 3% of the sample. Twelve percent of affected children died in infancy and 29% of surviving patients had developmental deficits/mental retardation. Although 15% of patients had growth retardation, an overgrowth pattern was seen in 9%. The data from this comprehensive review especially the developmental outcome should be added to the teratogenic risk, that arises in association with the use of VPA during pregnancy.

Complex limbal choristomas in linear nevus sebaceous syndrome

Objective This study aimed to describe the clinical and histopathologic findings in four patients with complex limbal choristomas associated with linear nevus sebaceous syndrome (LNSS), a rare disorder including nevus sebaceous, seizures, and mental retardation, and often accompanied by ocular anomalies. Design Small observational case series. Methods A retrospective review of the clinical and histopathologic records of four patients. Results Each of four patients had complex limbal choristomas in the setting of clinical and histopathologic LNSS. The limbal choristomas were multiple in three patients and bilateral in two patients. Most choristomas involved the superotemporal limbus (6 of 10), although nasal (3 of 10) and inferior (1 of 10) limbal tumors also were present. Three patients had significant corneal astigmatism or involvement of the central cornea requiring surgical removal of their choristomas, one accompanied by a lamellar keratoplasty and another accompanied by two consecutive penetrating keratoplasties. Each graft eventually vascularized, reducing vision. One patient’s vision was limited by amblyopia and another by occipital cortical dysgenesis with visual impairment. Histopathologic examination of the excised choristomas showed foci of lacrimal gland (3 of 4 patients), adipose tissue (3 of 4), neural tissue (1 of 4), cartilage (1 of 4), lymphoid follicles (1 of 4), skin adnexal tissue (1 of 4), and smooth muscle (1 of 4). Other associated ocular findings included an eyelid mass (1 of 4), colobomas of the eyelid (3 of 4), colobomas of the choroid and retina (2 of 4), nonparalytic strabismus (2 of 4), scleral ectasia (1 of 4), partial oculomotor palsy with ptosis and anisocoria (1 of 4), microphthalmia (1 of 4), and cortical visual impairment (1 of 4). Conclusions Complex limbal choristomas, although rare, can occur in the setting of LNSS and can be associated with multiple ocular and systemic abnormalities. Visual prognosis appears poor in most cases despite aggressive management.

Bilateral clinical anophthalmos

We report on the risk factors, associations and outcome of 5 children with bilateral clinical anophthalmos. Our study showed no gestational, environmental or hereditary association but confirmed strong association with multiple systemic abnormalities.

Left-right asymmetry of a nodal-related gene is regulated by dorsoanterior midline structures during Xenopus development.

Development of asymmetry along the left-right axis is a critical step in the formation of the vertebrate body plan. Disruptions of normal left-right patterning are associated with abnormalities of multiple organ systems, including significant congenital heart disease. The mouse nodal gene, and its homologues in chick and Xenopus, are among the first genes known to be asymmetrically expressed along the left-right axis before the development of organ asymmetry. Alterations in the expression pattern of mouse nodal and the chick homologue (cNR-1) have been associated with defects in the development of left-right asymmetry and cardiac looping (Levin, M., Johnson, R. L., Stern, C. D., Kuehn, M. and Tabin, C. (1995) Cell 82, 803-814; Collignon, J., Varlet, I. and Robertson, E. J. (1996) Nature 381, 155-158; Lowe, L. A., Supp, D. M., Sampath, K., Yokoyama, T., Wright, C. V. E., Potter, S. S., Overbeek, P. and Kuehn, M. R. (1996) Nature 381, 158-161). Here, we show that the normal expression patterns of the Xenopus nodal-related gene (Xnr-1) are variable in a large population of embryos and that Xnr-1 expression is altered by treatments that perturb normal left-right development. The incidence of abnormal Xnr-1 expression patterns correlates well with cardiac reversal rates in both control and experimentally treated Xenopus embryos. Furthermore, dorsal midline structures, including notochord and/or hypochord and neural floorplate, regulate Xnr-1 expression prior to the specification of cardiac left-right orientation by repression of Xnr-1 expression in the right lateral plate mesoderm during closure of the neural tube. The correlation of Xnr-1 expression and orientation of cardiac looping suggests that Xnr-1 is a component of the left-right signaling pathway required for the specification of cardiac orientation in Xenopus, and that dorsal midline structures normally act to repress the signaling pathway on the right side of the embryo.

Microdeletion of Chromosome 7P Syndrome Ocular Manifestations

Several syndromes have been associated with microdeletions of the autosomes. These syndromes are diverse in their morphology and frequently manifest abnormalities of the ocular adnexa. A child with an uncommon microdeletion of the short arm of chromosome 7P presented initially with congenital myogenic ptosis. After multiple systemic abnormalities were found during a routine examination, the child was referred for genetic evaluation where the defects were incidentally found. The child responded well with a fascia lata frontalis sling. The genetic disorder is discussed with an emphasis on the ophthalmologic findings.

Antibody to silicone and native macromolecules in women with silicone breast implants.

Silicone implants have been associated with the development of multiple organ system abnormalities, including rheumatic disorders, nervous system, pulmonary dysfunction associated with autoantibodies and abnormalities of cellular immunity. In this regards a number of case reports and series of articles have been described. We hypothesized that an immune reaction to silicone breast implants would include the host reactivity against silicone and the macromolecules within the microenvironment of the implant, and these autoantibodies may react with other tissue antigens far from the site of the implant. To test this hypothesis 520 Symptomatic women with Silicone Implants which have developed Silicone related Immunological disorders and have typically complained of breast pain, Myalgia-Arthralgia, fatigue, or generalized pain, were examined by their physician. Blood samples were obtained and examined for the presence of Silicone antibodies, Myelin Basic Protein and human serum albumin antibodies. These samples were then compared to 520 matched controls without implants. At least at the level of two standard deviation silicone specific antibodies, IgG, IgA IgM, IgE and IgG+IgA+IgM antibodies were detected above the mean of normal controls. When these antibodies were classified based on the specialty of the examining physician, the % of patients with Silicone Antibodies were varied; general practice 51.6, Rheumatology 58.7, and Plastic Surgery 83.3, which may relate to the severeness of the disease. Being that a large % of patients demonstrated very high levels of Myelin Basic Protein Antibodies, possible cross reactive antibodies were sought. However, absorption of highly positive sera for Silicone Antibodies with MBP did not change the levels of Silicone Antibodies. On the other hand, Silicone-HSA was able to reduce the antibody values significantly. This reduction in antibody levels by Silicone is the best indication for the specificity of these antibodies. Moreover when data for silicone antibodies and MBP antibodies was analyzed in patients some with high and others with medium or low levels of silicone antibodies, MBP antibodies did not correspond to the silicone antibody levels. Similarly human serum albumin antibodies which was significantly higher in patients with silicone implants did not correlate with levels of silicone antibodies. These results indicate that immune reaction to silicone and different tissue antigens do occur and they are initiated through different mechanisms. And since predominant antibody class against silicone, MBP and HSA was IgM, clonal activation of IgM is possible which certainly warrants further investigation.

Central and Peripheral Nervous System Demyelination After Infection With Mycoplasma pneumoniae: Evidence of an Autoimmune Process

We have reported a unique case of multiple central and peripheral nervous system abnormalities after a serologically documented infection due to Mycoplasma pneumoniae. The evidence suggests that this organism is capable of causing demyelination, probably through an autoimmune process. This case may help to provide further insight into the pathogenetic mechanisms involved in other demyelinating diseases in which the triggering exogenous agent is unknown. Certainly this case demonstrated that both central and peripheral nervous system demyelination can occur and that patients with M pneumoniae infections should be observed closely for possible development of neurologic symptoms.

Infection in utero: US findings in 19 cases.

The results of antenatal sonographic studies of 19 fetuses with congenital infections were retrospectively reviewed by the authors. Recognizing the significance of these antenatal sonographic findings is important because in utero infections can have devastating effects on the developing fetus. An infectious viral agent was isolated in laboratory tests at birth in 11 patients, and the effects of a viral agent were proved clinically in eight. Antenatal sonography demonstrated abnormalities in 18 fetuses: Multiple organ systems were affected in 47%; intracranial abnormalities, cardiac abnormalities, and parenchymal calcifications occurred in 42%, 37%, and 32%, respectively; large placentas were seen in 32%; and the volume of amniotic fluid was decreased in 37% and increased in 37%. Sixty-three percent of fetuses were either aborted or died at birth; the 37% that lived were all developmentally impaired. On the basis of these sonographic, laboratory, and clinical findings, the authors conclude that when multiple organ system abnormalities are found at antenatal ultrasound, the presence of an in utero infection should be considered. The parents should be informed that there is a poor prognosis for any fetus demonstrating such abnormalities.

Disseminated granulomatous disease (BCGosis) following chemoimmunotherapy for ovarian carcinoma

The use of BCG (bacille Calmette Guérin) in conjunction with cytotoxic chemotherapeutic agents has been advocated in patients with ovarian carcinoma. We describe a patient with stage III, grade I, endometrioid carcinoma of the ovary treated with cisplatin, doxorubicin, cyclophosphamide, and BCG. Following one course of therapy she presented with an elevated temperature, purpuric skin rash, abnormal liver function tests and hematological indices, and multiple organ failure resulting in sepsis and death. At autopsy, disseminated noncaseating granulomas were found in the lungs, hilar lymph nodes, liver, and spleen. Metastatic carcinoma was not present in these organs. This report describes the rapid onset of a disseminated BCG infection (BCGosis) in a patient with ovarian carcinoma receiving chemoimmunotherapy. Clinical recognition of BCGosis in immunocompromised patients is difficult but should be considered in the differential diagnosis of patients presenting with unexplained febrile illness, functional abnormalities in multiple organ systems, and a history of immunotherapy with BCG. Appropriate specimen collection is emphasized.

Classification of chromosomal eye syndromes.

Human chromosome disease arises from a change in the number or structure of one or more chromosomes. The multiple genes represented in the duplicated or deleted chromosomes are not usually defective and any systemic abnormalities can be attributed to a change in gene dosage. Banding techniques are now commonly used to identify each chromosome and the specific chromosome duplication and deletion and structural rearrangements can now be identified unambiguously. Most ocular abnormalities have occurred in patients with chromosomal defects. Major ocular abnormalities, such as anophthalmia, cyclopia, retinoblastoma, microphthalmia, corneal opacities, coloboma, cataracts, intraocular cartilage, retinal dysplasia and absent optic nerves; and, minor abnormalities, such as ptosis, abnormal eyelid fissures, and Brushfield spots are present in individuals with abnormal chromosomes. The chromosome errors are usually present in all somatic tissues. consequently, multiple tissue abnormalities would be expected in most patients with chromosome abnormalities. Mental retardation is very common in those patients with abnormalities of autosomes. Therefore, it is unlikely that an isolated single clinical or histopathological ocular abnormality will be the result of a chromosome error. However, if the individual has multiple systemic abnormalities, then a chromosome error can be considered reasonably. Any chromosome disorder can be identified correctly by an appropriate banding chromosome determination on the affected individuals. With the possible exception of the association of 13q 14- and retinoblastoma, there does not appear to be any pathognomonic ocular abnormalities that occur in individuals with chromosome errors.

Biogenic amine hypothesis of affective disorders

Many lines of evidence suggest that effective disease is a heterogenous group of disorders. Pharmacologic, amine metabolite and neuroendocrine studies have aided in the tentative identification of two subtypes of depressive illness. One subtype may show an abnormality of central NE systems; the other, an abnormality of central 5-HT systems. Manic patients appear to manifest abnormalities of multiple systems biologically which may be related to a disturbance of ion exchange in a variety of cells both within and outside of the CNS. The understanding of these processes is far from complete and are the subject of continued scrutiny.

Biology of Drowning

The near-drowning victim must be treated immediately for ventilatory insufficiency, hypoxia, and the resulting acidosis. The cause and pathophysiologic changes of pulmonary insufficiency vary, depending on the tpe and volume of fluid aspirated. Success or failure of the overall resuscitative effort frequently depends on the adequacy of prompt emergency resuscitation and on effective intensive pulmonary care. Each patient should be evaluated and treated individually, since abnormalities of multiple organ systems can occur, their degree and form varying considerably from patient to patient (28).

System-Structured Management of Acutely Ill Surgical Patients

The management of surgical patients requiring intensive care is complicated by abnormalities in multiple body systems. An effective method of organizing data collection and treatment is essential. The widely applied "problem-oriented" approach is not entirely satisfactory in the context of surgical intensive care. An alternative method is presented in which management is structured by body systems. The function of each system is analyzed and a plan for each is defined. Data display is arranged by systems rather than problems and is compatible with modern computer technology. A surgical patient under treatment for pancreatitis is presented to illustrate this approach. Experience with 220 patients on a residency teaching service supports the impression that system-structured management is an effective method of managing the course of an acutely ill patient and should be widely applicable to such patients in any general surgical environment.

Sclero-cornea and defective mesodermal migration.

A 5-month-old boy with bilateral sclero-cornea, multiple systemic abnormalities, and normal karyotype had his left eye removed after corneal perforation. Histopathological examination of the enucleated eye revealed an irregular corneal epithelium, absent Bowman's membrane, thickened and vascularized stromal lamellae, absent Descemet's membrane and endothelium, no angle structures, hypoplasia of the iris and ciliary body, and total kerato-iridic adhesions. A profound defect in embryogenesis due to defective mesodermal migration during the earliest phase of mesoderm differentiation is postulated as the causative factor in this case.

THE RELATIONSHIP BETWEEN VITAMIN D AND THE CRANIOFACIAL AND DENTAL ANOMALIES OF THE SUPRAVALVULAR AORTIC STENOSIS SYNDROME

There is evidence that a derangement in vitamin D metabolism on the part of the mother, the fetus, or both may be responsible for supravalvular aortic stenosis, especially when the latter is associated with infantile hypercalcemia. It has been shown that the offspring of rabbits given large amounts of parenteral vitamin D throughout pregnancy may be born with aortic lesions resembling supravalvular aortic stenosis as seen in man. The present study was designed to explore experimentally the relationship between exposure to excessive amounts of vitamin D during pregnancy and the development of the craniofacial complex and dentition because children with the multiple system abnormalities of the supravalvular aortic stenosis syndrome (SASS) share a characteristic craniofacial appearance and exhibit, in common, many abnormalities of dentition. Examination of their jaws and teeth reveals hypoplasia of the mandible, congenital absence of teeth (usually the lateral incisors and second premolars of the maxilla), microdontia, dysgnathia, enamel hypoplasia, and a narrowed occlusal table. In the present study, analogous findings were observed in rabbit offspring whose mothers received large amounts of vitamin D during pregnancy. The most marked functional accompaniment of these abnormalities was severe malocclusion of the teeth. Peculiar facies, premature closure of the cranial bones, strabismus, odd shaped ears, and a low birth weight were additional features of SASS that were noted in many test animals. Buphthalmos was also noted occasionally, probably related to maldevelopment of the bony ocular orbits. Thus, these experimental observations suggest that the cranial, facial, and dental peculiarities as well as the aortic lesion of the supravalvular aortic stenosis syndrome may be related to a derangement in vitamin D metabolism during pregnancy.