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PubMed1987

Haem-rotational disorder in monomeric allosteric cyano-Met insect haemoglobins monitored by resonance Raman spectroscopy.

The haem-rotational disorder (insertion of haem into globin rotated about the alpha, gamma-meso axis by 180 degrees) has been investigated in the cyano-Met form of the monomeric allosteric insect haemoglobins, CTT III and CTT IV, by resonance Raman spectroscopy. The effect of haem disorder on the resonance Raman spectra has been observed in proto-IX, deutero-IX, and meso-IX CTTs. Most importantly, in the absence of overlapping vinyl vibrations, we have identified two Fe-C-N bending vibrations at 401 cm-1 and 422 cm-1 (pH 9.5) for 57Fe deutero-IX CTT IV ligated with 13C15N-, which are attributed to the two haem-rotational components. One Fe-C-N bending mode at 422 cm-1 shows a pH-induced shift to 424 cm-1 (pH 5.5) indicating the t----r conformational transition, whereas the other bending mode is pH-insensitive, representing a non-allosteric component. By replacing the unsymmetrical porphyrins with the "symmetrical" protoporphyrin-III we eliminate the haem disorder. Then, sharpening of the Fe-N epsilon(His) (at 313 cm-1) and Fe-CN (at 453 cm-1) stretching modes is observed and a single Fe-C-N bending mode (at 412 cm-1) appears. In cyano-Met proto-IX CTT III two vinyl bending vibrations at 412 cm-1 and 591 cm-1 assigned by deuteration of the vinyl groups also reflect the haem disorder. The 412 cm-1 vinyl vibration is intensity-enhanced via through-space coupling with one of the Fe-C-N bending modes (at 412 cm-1). In the cyano-Met form of proto-III CTT III this vinyl vibration is shifted to 430 cm-1 resulting in a dramatic drop in intensity. It is most likely that the specific vinyl-protein interaction at position 4 in one of the haem-rotational components is the origin of the coupling between the Fe-C-N and vinyl bending modes. The Fe-N epsilon(proximal His) and the Fe-CN stretching vibrations as well as the Fe-C-N bending vibration have been identified by 54Fe/57Fe and 13C15N/12C15N/13C14N/12C14N isotope exchange.

Animals↗

PubMed2000

Goitrogenesis during pregnancy and neonatal hypothyroxinaemia in a borderline iodine sufficient area.

OBJECTIVE: Severe iodine deficiency disorders (IDDs) may have been eradicated in many parts of the world, but milder forms still exist and may escape detection. We evaluated the impact of pregnancy on the maternal and fetal thyroid axis in Hong Kong, a coastal city in southern China with borderline iodine intake. DESIGN: A prospective study performed in a maternity hospital. PATIENTS: Two hundred and thirty pregnant women were prospectively studied and their neonates assessed at birth. MEASUREMENTS: Urine iodine concentration, thyroid function tests and thyroid volume (TV) by ultrasound were determined in the mothers during pregnancy and up to 3 months postpartum and in the neonates. RESULTS: Increased urinary iodine concentration was seen from first trimester onwards and the proportion of women having urine iodine concentration of < 0.4 micromol/l decreased from 11.3% in the first trimester to 4.7% in the third trimester. There was progressive reduction in circulating fT4 and fT3 concentrations and free thyroxine index (FTI) with increasing gestation and the percentage of women having subnormal levels at term were 53.2%, 61.1% and 4.8%, respectively. The serum TSH concentration during pregnancy doubled towards term. In the first trimester, multiparous women had significantly larger TV than the nulliparous women (P < 0.001). By the third trimester, TV had increased by 30% (range 3-230%) so that the goitre incidence was 14.1%, 21.8%, 25.9% during the three trimesters of pregnancy, and 24.3% and 21.9% at 6 weeks and 3 months postpartum (ANOVA, P < 0.05). The change in thyroid volume during pregnancy correlated positively with the change in thyroglobulin (r = 0.225, P < 0.002) and negatively with urinary iodine concentration (r = - 0.149, P < 0.02). Fourteen women with excessive thyroidal stimulation in the second trimester (defined as those with thyroglobulin (Tg) concentrations in the highest tertile and FTI in the lowest tertile) were found to have lower urine iodine concentrations and larger TV (both P < 0.005) throughout pregnancy, and their neonates had higher cord TSH (P < 0.05), Tg (P < 0.05) and slightly larger TV (P = 0.06) as compared to the findings in 216 pregnant women without evidence of thyroid stimulation. Seven neonates (50%) born to these women had subnormal fT4 levels at birth. CONCLUSION: In a borderline iodine sufficient area, pregnancy posed an important stress resulting in higher rates of maternal goitrogenesis as well as neonatal hypothyroxinaemia and hyperthyro- trophinaemia. An adequate iodization program is necessary to eliminate iodine deficiency disorders during pregnancy.

Analysis of Variance↗

PubMed2001

Myoclonus of peripheral origin: case secondary to a digital nerve lesion.

We present a patient with myoclonus of the left hand appearing 1 month after surgical correction of a stenosing tenosynovitis of the thumb. An extensive fibrosis of the external palmar digital nerve was shown, and the successful liberation of this median nerve terminal branch completely and rapidly eliminated the movement disorder.

Adolescent↗

PubMed1995

Amelioration of autoimmune reactions by antigen-induced apoptosis of T cells.

We have shown that T cells vigorously cycling in response to growth lymphokines are driven into apoptosis by potent TCR restimulation. This process, termed propriocidal regulation, appears to be a normal feedback inhibitory mechanism to prevent excessive T cell proliferation and lymphokine production. Exposure of T cells to repeated high dose antigen treatments creates the conditions just described by activating T cells, and stimulating the production of growth lymphokines and their receptors. High growth lymphokine levels induced by the large amount of antigen present, stimulate vigorous cycling. The continued presence of high antigen levels subjects the cycling T cells to strong TCR restimulation as they enter the vulnerable S phase, inducing apoptosis in T cells responsive to the administered antigen. Thus, simple, repetitive, intravenous administration of high dose antigen may be used to delete potentially destructive clones of T cells, resulting in a state of peripheral tolerance. This has obvious therapeutic potential in disorders where the elimination of pathogenic T cell clones could be beneficial. We have described in EAE, an animal model for MS, that high dose MBP therapy is effective in preventing CNS pathology and the onset of disease as well as reducing the severity of the clinical symptoms of established EAE. We are currently involved in expanding this approach to other animal models of autoimmunity and graft rejection, as well as refining the immunotherapy in the EAE model with the objective of developing a clinical therapy for human demyelinating disease.

Antigens↗

PubMed1991

Calcipotriol (MC 903): pharmacokinetics in rats and biological activities of metabolites. A comparative study with 1,25(OH)2D3.

Calcipotriol (MC 903) is a novel analogue of the physiologically active metabolite of vitamin D3, 1 alpha,25-dihydroxycholecalciferol [1,25(OH)2D3]. MC 903 and 1,25(OH)2D3 have similar effects on cell proliferation and cell differentiation in vitro using the human histiocytic lymphoma cell line U 937, but in vivo MC903 has 100-200 times less effect on calcium metabolism. To elucidate this difference, the pharmacokinetic profiles after a single intravenous dose (50 micrograms/kg) of the two compounds to rats were compared. The area under the serum level/time curve (AUC) was more than 100 times higher for 1,25(OH)2D3 than for MC903 and the rate of clearance was more than 100 times higher for MC903 than for 1,25(OH)D3. Serum from MC903 or 1,25(OH)2D3 dosed rats (i.v. 10 micrograms/kg) was investigated for biological activities by incubation of U 937 cells with serum collected 0-24 hr after drug administration. Serum from MC903 dosed rats had an effect only when collected shortly after dosing, whereas serum from 1,25(OH)2D3 dosed rats had an effect when collected up to 4 hr after dosing. The biological effects on the U937 cells of the two major metabolites of MC903 (MC 1046 and MC 1080) were investigated. The metabolites had effects that were more than 100 times weaker than those of the parent compound. The effect of MC903 on proliferative disorders, its fast elimination and the formation of inactive metabolites makes MC903 suitable for topical treatment of psoriasis.

Animals↗

PubMed2006

Polycystic ovary syndrome in men: Stein-Leventhal syndrome revisited.

Polycystic ovary syndrome (PCOS), also referred to as Stein-Leventhal syndrome, is one of the most common endocrinopathies. It is characterized by hyperandrogenism, hyperinsulinemia, central obesity, polycystic ovaries, and anovulation. However, some of these manifestations, including the polycystic ovaries, are neither specific for the disorder, nor found in all affected individuals. PCOS appears to be due to one or more primary defects in the upstream gonadotropin/androgen and/or insulin pathway, with the polycystic ovaries being one of many downstream manifestations. Yet, the pathophysiology of PCOS is not completely elucidated. Since the primary defect underlying PCOS may be an upstream endocrine and/or metabolic disturbance, rather than a defect in the ovaries themselves, we hypothesize that this aberration can also arise in men and that the absence of polycystic ovaries in men with other stigmata of the disorder should not eliminate the diagnosis. Our hypothesis is supported by the observation that a genetic susceptibility to PCOS exists, and that PCOS-type manifestations are not limited to women. Indeed, male relatives may suffer from insulin resistance, obesity, diabetes mellitus, and cardiovascular disease. Therefore, recognition of this syndrome in men is important, since pharmacologic treatments identified for women with PCOS may alleviate metabolic problems related to insulin resistance and its sequelae in men with a similar underlying defect. We suggest that first-degree relatives of patients with PCOS should be examined not only for phenotypic features characteristic of PCOS but also for biochemical evidence of hyperinsulinemia and hyperandrogenism. In addition to examining these individuals for obesity, the women should be evaluated for hirsutism and the men should be screened for early-onset male-pattern alopecia and excess hairiness. Serologic evaluation should included the ratio of fasting levels of glucose to insulin, a glucose tolerance test, the free testosterone level and the sex hormone-binding globulin level. Finally, both male and female first-degree relatives of patients with PCOS should be tested for the underlying molecular defect(s) of this condition, once it is identified. As new treatments for PCOS emerge, e.g. insulin-sensitizing drugs, it will be important to determine if these treatments have beneficial effects on the metabolic symptoms and complications in all afflicted patients, regardless of gender.

Female↗

PubMed2001

Nosocomial pneumonia. Diagnostic and therapeutic considerations.

Many patients with presumed nosocomial pneumonia probably have infiltrates on the chest radiograph, fever, and leukocytosis resulting from noninfectious causes. Because of the high mortality and morbidity associated with nosocomial pneumonias, however, most clinicians treat such patients with a 2-week empiric trial of antibiotics. Before therapy is initiated, the clinician should rule out other causes of pulmonary infiltrates, fever, and leukocytosis that mimic a nosocomial pneumonia (e.g., pre-existing interstitial lung disease, primary or metastatic lung carcinomas, pulmonary emboli, pulmonary drug reactions, pulmonary hemorrhage, collagen vascular disease affecting the lungs, or congestive heart failure). If these disorders can be eliminated from diagnostic consideration, a 2-week trial of empiric monotherapy is indicated. The clinician should treat cases of presumed nosocomial pneumonia as if P. aeruginosa were the pathogen. Although P. aeruginosa is not the most common cause of nosocomial pneumonia, it is the most virulent pulmonary pathogen associated with nosocomial pneumonia. Coverage directed against P. aeruginosa is effective against all other aerobic gram-negative bacillary pathogens causing hospital-acquired pneumonia. The clinician should select an antibiotic for empiric monotherapy that is highly effective against P. aeruginosa, has a good side-effect profile, has a low resistance potential, and is relatively inexpensive in terms of its cost to the institution. The preferred agents for empiric monotherapy for nosocomial pneumonia are cefepime, meropenem, and piperacillin. Single organisms are responsible for nosocomial pneumonia, not multiple pathogens. S. aureus rarely, if ever, causes nosocomial pneumonia but is mentioned frequently in studies based on cultures of respiratory tract secretions. S. aureus, unless accompanied by a necrotizing pneumonia with rapid cavitation within 72 hours, in the sputum indicates colonization rather than infection and should not be addressed therapeutically. Antibiotics associated with a high resistance potential should not be used as monotherapy or included in combination therapy regimens (i.e., ceftazidime, ciprofloxacin, imipenem, or gentamicin). Combination therapy is more expensive than monotherapy and is indicated only when P. aeruginosa is extremely likely, based on its characteristic clinical presentation, or is proved by tissue biopsy. Therapy should not be based on respiratory secretion cultures regardless of technique. Optimal combination regimens include cefepime or meropenem plus levofloxacin or piperacillin or aztreonam or amikacin. Nosocomial pneumonias usually are treated for 14 days. Lack of radiographic or clinical response to appropriate empiric nosocomial pneumonia monotherapy after 14 days suggests an alternate diagnosis. In these patients, a tissue biopsy specimen should be obtained to determine the cause of the persistence of pulmonary infiltrates unresponsive to appropriate antimicrobial therapy.

Anti-Bacterial Agents↗

PubMed1985

Secondary bonegrafting in unilateral cleft lip palate patients: indications and treatment procedure.

A consecutive series of 62 complete unilateral cleft lip and palate patients were investigated with respect to indication for a secondary bone grafting. 2 major indications for secondary bone grafting were established. One was a symptomatic oro-nasal fistula, the other one being a bony defect in the alveolar process, which could impair orthodontic treatment and prosthodontic rehabilitation in the cleft area. The average age for bonegrafting was 12 years. After surgery, fistula-related discomfort was eliminated and speech disorders were drastically reduced. Orthodontic uprighting of teeth and correction of mid-line deviations indicated in 50% of the patients were facilitated. In 10% of the cases with extensive defects in the alveolar process, the graft enhanced the possibility for later prosthodontic treatment. Secondarily, periodontal conditions improved. When bonegrafting was performed before canine eruption, total dental rehabilitation by orthodontic treatment was often sufficient, thus decreasing the need for later prosthodontic restoration of the cleft area. Patients who had surgery after eruption of the cleft side canine exhibited more complications. The optimal treatment sequence therefore appears to be transversal expansion of the maxilla in the late mixed dentition, followed by bone grafting. Maxillary expansion must be retained until final orthodontic and prosthodontic treatment is carried out.

Adolescent↗

PubMed2000

Suicidal ideation in a random community sample: attributable risk due to depression and psychosocial and traumatic events.

OBJECTIVE: To determine the attributable risk for suicidal ideation of depression and psychosocial and traumatic events in a random and representative population. METHOD: Data were gathered from a random and representative sample of 2501 South Australians. Suicidal ideation and clinical depression were determined by the general health questionnaire (GHQ-28) and the short-form health survey (SF-12) respectively, and information regarding psychosocial stressors and traumatic events was collated. These data were subjected to univariate and multivariate analyses to determine the population-attributable risks for suicidal ideation. RESULTS: Overall, 5.6% of men and 5.3% of women had suicidal ideation. Univariate analyses demonstrated a significant attributable risk for suicidal ideation for depression and the majority of the psychosocial and traumatic events. Multivariate analysis demonstrated that clinical depression remained significantly associated with suicidal ideation, with a population-attributable risk of 46.9%. Because of the small number of people in the population who experience both suicidal ideation and specific events, multivariate analysis could not be applied to individual events. However, even when the psychosocial events were summed, they no longer remained significantly associated with suicidal ideation, whereas the summation of traumatic events remained significant, with a population-attributable risk of 38.0%. CONCLUSIONS: These results confirm the importance of traumatic events as significant factors in contributing to suicidal ideation. However, of even greater importance is that they indicate, unequivocally, the magnitude of the contribution of clinical depression to suicidal ideation, with the population-attributable risk of depression indicating that elimination of mood disorders would reduce suicidal ideation by up to 46.9%.

Adolescent↗

PubMed2003

Paradoxical arterial emboli causing acute limb ischemia in a patient with essential thrombocytosis.

Acute arterial occlusion can be the result of acute thrombosis or systemic embolism. Paradoxical embolism of a venous thrombosis through a right-to-left shunt is an important cause of acute limb ischemia. We describe a young patient with acute limb ischemia who was found to have multiple deep venous thromboses causing arterial embolization through a patent foramen ovale. Essential thrombocytosis was found to be the risk factor for venous thromboses in this patient. The patient was managed with embolectomy and anticoagulation along with chemotherapeutic cytoreduction of platelet count. This case illustrates the importance of considering the systemic embolism as a cause of acute arterial occlusion. The presence of a hypercoagulable status such as chronic myeloproliferative disorder does not eliminate the possibility of systemic embolism in the event of acute arterial occlusion. Patients presenting with acute limb ischemia should be evaluated for embolic sources. The presence of deep venous thrombosis in such a patient should prompt the evaluation for a patent foramen ovale.

Adult↗

PubMed2000

Gelatinous transformation of the bone marrow: the spectrum of underlying diseases.

Gelatinous bone marrow transformation (GMT) is a rare disorder of unknown pathogenesis, characterized by fat cell atrophy, focal loss of hematopoietic cells, and deposition of extracellular gelatinous substances, which histochemically are mucopolysaccharides, rich in hyaluronic acid. To elucidate the conditions in which GMT develops, 155 cases of GMT that had been found in our archives among 80,000 marrow biopsies were revised. GMT occurred exclusively in adults, more often in males (n = 101) than in females (n = 54). Incidence and severity of GMT lesions were maximal in young adults. The spectrum of underlying diseases was heterogeneous and age-dependent. Anorexia nervosa, acute febrile states, and AIDS in younger ages (<40 years), alcoholism and lymphomas in middle ages, and carcinomas, lymphomas, and chronic heart failure in older ages (>60 years) were most commonly associated with GMT. Seventy-eight percent of patients with GMT showed weight loss; 81% were anemic. GMT in some cases may be a reversible lesion if the underlying disorder can be eliminated. In conclusion, GMT represents an indicator of severe illness in a patient but is not specific for a particular disease. Because GMT develops in different pathologic conditions, we suggest that basic bioregulatory processes play a role in its pathogenesis.

Acquired Immunodeficiency Syndrome↗

PubMed1999

B-DNA at atomic resolution reveals extended hydration patterns.

Despite the importance of hydration around DNA in the understanding of its conformation and interactions with other molecules in many biological processes, only limited atomic resolution information is available. Crystal-engineering techniques, which were originally developed to mimic DNA base triplets in a crystal lattice, also eliminate the rotational disorder of oligonucleotides around their helical axis and thereby enhance the resolution of the structure analysis. We have determined the low-temperature crystal structure of the synthetic DNA decamer d(GGCCAATTGG) at atomic resolution (1. 15 A) using 17700 reflections and have characterized the highly organized hydration patterns in both grooves. The narrow d(AATT) minor groove is occupied by an 'extended hydration spine' alternately bridging base pairs and phosphate O1P atoms of opposite strands, while a distinctive pattern of parallel water ribbons is observed in the major groove. This analysis provides structural insight into the correlation found between narrow minor-groove width and occurrence of the B(I) conformation and can be used to design new minor-groove binders. By their location between adjacent helices, two fully hydrated magnesium ions further stabilize the crystal packing. The structure also provides details of the hydration and conformation of G.GC triple helices.

Crystallization↗

PubMed2000

Estimation of salt intake and recommendation for iodine content in iodized salt in Mongolia.

In 1996, the Mongolian Government pledged to eliminate iodine deficiency disorders by 2001 using salt iodization as its primary strategy. Iodine content in salt was set at 50 +/- 10 PPM based on an assumption of 5 g of daily salt intake. In 1998, the authors suspected that salt intake was more than 5 g and that pregnant women consumed more salt than non-pregnant women. Over 1,600 adults of both sexes were studied in five provinces. In this study we estimated salt intake based on urinary excretion of sodium and creatinine. A formula was used to calculate salt intake from excreted volumes of sodium and creatinine. Average values for pregnant women, non-pregnant women, and men, were found to be 15.6 g (n = 499), 12.6 g (n = 598), and 14.6 g (n = 571), respectively. We concluded that appropriate iodine content in salt should range from 20 to 40 PPM. It is recommended that health education regarding proper levels of salt intake be carried out with the general public, with emphasis on pregnant women.

Adolescent↗

PubMed1980

A multimodal approach to elimination of stuttering.

Various approaches have been used in the treatment of stuttering. However, none of these approaches have been systematically incorporated via a multifaceted treatment program for the elimination of this disorder. The following case of a 15-yr.-old stutterer is presented to illustrate Lazarus' Multimodal Behavior Therapy Model, which is proposed to integrate various procedures whose singular effectiveness has been demonstrated.

Adolescent↗

PubMed2005

The induction of inflammation by adenovirus vectors used for gene therapy.

The ability to repair or enhance an individual's genetic make-up provides the sublime opportunity to ameliorate or eliminate many clinical disorders that affect mankind. Gene therapy is thus a revolutionary clinical strategy that may potentially treat an array of genetic and non-genetic diseases, as well as a novel method for drug delivery and vaccination. To these ends, adenovirus vectors are currently the most promising means to deliver specific genes of interest into target cells of the patient. A major limitation of the use of adenovirus vectors in clinical trials, however, is the rapidly induced inflammatory response against these infectious particles. This review aims to describe the cellular and molecular mechanisms involved in the adenovirus-mediated inflammatory response.

Adenoviridae↗

PubMed1999

[Treatment of intestinal dysbacteriosis in children with diabetes mellitus].

The use of the probiotic Acylact in combination with Viferone containing human recombinant interferon-alpha 2 in the treatment of intestinal dysbacteriosis in children with insulin-dependent diabetes mellitus (IDDM) was shown to be highly efficient. Elimination of microecologic disorders in the intestine was accompanied in all the children by immune rearrangements. The quantity of secretory and serum immunoglobulins and complement increased and the white blood cell chemiluminescence proved to be higher. The correction of the immune status of the children with IDDM resulted in a certain decrease of glycemia. The data are indicative of the fact that such a treatment of intestinal dysbacteriosis in children with IDDM is promising.

Adolescent↗

PubMedDate not supplied

[Use of gutimin for the treatment of experimental traumatic shock].

The guthymine medication of a severe shock in rats started 10-20 minutes after injury is shown to eliminate energy metabolism disorders in the brain, liver and kidneys. In the brain of the guthamyine treated rats even a somewhat reduced adenosinetriphosphate content was demonstrable. Administration of guthymine together with polyglucin to cats in a torpid phase of the shock did not effect treir survival, but shortened the life-span of the test animals as compared to controls (receiving polyglucin alone). With guthymine addid to polyglucin the lactate and pyruvate concentration in the blood remained unchanged.

Amidines↗

PubMed1992

The effect of patellar button placement and femoral component design on patellar tracking in total knee arthroplasty.

The effects of patellar button position and femoral component design on patellar tracking were investigated roentgenographically and arthroscopically using fresh-frozen adult anatomic specimen knees. Patellar tracking was evaluated for medial/lateral position and tilting angle deviation by comparing preoperative normal values to total knee replacement performance with the following variables: (1) femoral component design; symmetrical total condylar type with a 3-mm central patellar groove and a component with a 3-mm raised lateral patellar flange and 1-mm deepened patellar groove; and (2) patellar button placement; central insertion; and 10-mm medialized insertion. In the roentgenographic study, medialized position of the patellar button allowed the bony portion of the patella to assume its normal lateral position and tilt throughout the knee range of motion. A combination of medialized position of the patellar button and deepening of the patellar groove provided the most anatomically correct position and the most normal tilting of the bony structure of the patella. In the arthroscopic study, the centralized patellar position caused significant lateral tracking and subluxation relative to the femoral component, whereas the medialized position eliminated this tracking disorder. Deepening the patellar groove minimized the intraarticular tracking abnormality and constrained the patellar button in the patellar groove. These results show that the position of the patellar button and femoral component design exert a major influence on patellar tracking.

Adult↗