Synthesis and antimicrobial testing of novel oxadiazolylbenzimidazole derivatives

OBJECTIVE: To chart the subtle neurological abnormalities in patients with asbestosis relative to possible development of cancer. METHODS: In 1979-81 a standardised neurological examination was made of 115 patients with asbestosis who carried a high risk of occupational cancer and their cancer morbidity was analysed 15 years later. RESULTS: Slight disturbances of unknown aetiology were found in the central nervous system (CNS) of 33 and in the peripheral nervous system (PNS) of 41 patients. Of these 17 had disturbances of both the CNS and PNS. This cohort was followed up to the end of 1994. During this time 47 of the patients developed cancer. Statistical analyses showed that disturbances of the CNS such as psycho-organic syndrome, cerebellar dysfunction, and motor disturbances of unknown origin were significantly associated with cancer, whereas no such association was found for peripheral neuropathy. Interaction between the radiological progression of asbestosis and disturbances of the CNS was an even stronger predictor of cancer. CONCLUSIONS: It seems that slight disturbances of the CNS are predictors of development of cancer. Whether or not these disturbances are manifestations of involvement of a paraneoplastic nervous system or some factor associated with progression of asbestosis remains open.     

Renal pathology of VTEC related HUS

Renal histopathology of verotoxin producing escherichia coli(VTEC) related hemolytic uremic syndrome (HUS) was described. Endothelial damage is expressed in renal small arteries and glomeruli as luminal narrowing due to endothelial swelling and subendothelial edema. Extracellular matrix shows reticularization and/or mesangiolysis in glomeruli. Although HUS and thrombotic thromocytopenic purpura (TTP) is recently considered as a single entity, the tissue expression is different. In the latter endothelial proliferation is profound resulting in arteriolar deteriolation such as glomeruloid structure.     

Inflammatory mediators in Escherichia coli O157:H7 hemorrhagic colitis and hemolytic-uremic syndrome

BACKGROUND: Recent experimental data suggest that the inflammatory response of the host to verotoxin and/or lipopolysaccharides of Escherichia coli is involved in the pathophysiology of verotoxin-producing E. coli (VTEC) infections. METHODS: We measured the circulating concentrations of cytokines [TNF-alpha, interleukin (IL)-1-beta, IL-1 receptor antagonist (Ra), IL-6, IL-8, IL-10] and soluble leukocyte adhesion molecules (L-selectin, P-selectin, E-selectin, intracellular cell adhesion molecule-1, vascular cell adhesion molecule-1) by sandwich enzyme-linked immunosorbent assay among (1) normal controls (n = 12), (2) disease controls with hemorrhagic colitis (HC) not associated with VTEC infections (n = 57), (3) patients with uncomplicated HC caused by E. coli O157:H7 (n = 30), and (4) children with hemolytic-uremic syndrome (HUS) (n = 28). Patients with HUS were matched with children who presented an uncomplicated HC caused by E. coli O157:H7 for the time interval elapsed between the onset of HC and that of blood sample collection. RESULTS: Concentrations of TNF-alpha and IL-1-beta were undetectable. Children with HUS were characterized by increased amounts of IL-6 and IL-8, lower values of soluble L-selectin as well as increased levels of IL-10 and IL-1Ra. The circulating concentrations of IL-1Ra were higher among children with O157:H7 HC who subsequently developed HUS. CONCLUSIONS: Increased pro- and antiinflammatory cytokine responses are produced by the host during the development of HUS among children with VTEC infections. Further studies are needed to determine their relative contribution to the pathophysiology of classic HUS.     

Cytokines in childhood hemolytic uremic syndrome and thrombotic thrombocytopenic purpura

Serum and urine cytokines were analyzed in children with hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). Interleukin-6 (IL-6) was elevated in the serum of 33 of 35 children with HUS (94%) and in 2 of 2 children with recurrent TTP. Serum IL-6 was higher in children with HUS who developed anuria, extrarenal manifestations during the acute phase of illness and/or chronic renal sequelae. Tumor necrosis factor-alpha (TNF-alpha) was detected in the serum of 7 patients with HUS (20%) and 1 patient with TTP. IL-6 and TNF-alpha were elevated in the urine of 4 of 4 children with HUS and 2 of 2 children with TTP. Urinary levels were higher than serum levels, suggesting local production of cytokines in the urinary tract. Sequential serum and urine samples showed that IL-6 levels varied with disease activity. IL-6 and TNF-alpha were not detected in the serum (n = 25) and urine (n = 15) of healthy children. We conclude that IL-6 in urine may be used to monitor disease activity in HUS and TTP.     

Renal transplantation in adults with thrombotic thrombocytopenic purpura/haemolytic-uraemic syndrome

BACKGROUND: Thrombotic thrombocytopenic purpura/haemolytic-uraemic syndrome (TTP/HUS) is a rare cause of renal failure in adults. There is little data concerning the outcome of adult patients who receive a renal transplant for TTP/HUS: METHODS: We have carried out a survey of 22 transplant centres in the USA to determine the outcome of patients who developed ESRD from TTP/HUS and latter received a renal transplant. RESULTS: Twelve of the 22 centres responded to our inquiry. Seven centres had not transplanted any patients with TTP/HUS, and five centres had transplanted a total of 24 grafts in 17 patients with TTP/HUS: Thirty-three per cent of patients demonstrated definite clinical and pathological evidence of recurrence of TTP/HUS: An additional 16% of patients demonstrated pathological evidence of possible recurrence of TTP/HUS in the absence of clinical manifestations. The overall 1-year graft survival rate was 42% and the 2-year graft survival rate was 35%. In our experience recurrence TTP/HUS was associated with universal graft failure. Although cyclosporin A does occasionally cause a thrombotic angiopathy in patients with no history of TTP/HUS, we found no evidence that it should be avoided in patients with a previous history of ESRD from TTP/HUS who subsequently receive a renal transplant. CONCLUSIONS: TTP/HUS frequently recurres in adults who receive a renal transplant, with a 2-year graft survival rate of 35%.     

Refractory angina despite patent coronary artery bypass grafts: treatment with transmyocardial laser revascularization and scintigraphic evidence of improved myocardial perfusion

Erdheim-Chester disease is a rare sporadic systemic histiocytic disease of unknown aetiology that affects multiple organ systems. The case records of all patients with Erdheim-Chester disease who had been seen at the Mayo Clinic between 1975 and 1996 were reviewed to assess the neurological manifestations of the disease. Two of 10 patients had neurological involvement. A 42 year old woman developed central diabetes insipidus and a progressive cerebellar syndrome. Brain MRI showed a lesion in the left pons with patchy gadolinium enhancement and T2 weighted signal abnormalities extending into both cerebellar peduncles and the medulla. Biopsy of the brainstem mass showed a xanthogranulomatous lesion. The second patient was a 53 year old man with retroperitoneal fibrosis secondary to xanthogranulomatous infiltration. Although he had no neurological symptoms and a normal neurological examination, MRI of the head showed multiple uniformly enhancing extra-axial masses along the dura of both convexities and the falx, and a mass in the left orbital apex. Both patients had the characteristic radiographic and bone scan findings of Erdheim-Chester disease. Review of the literature disclosed a wide variety of neurological manifestations in Erdheim-Chester disease. The most frequent CNS manifestations are diabetes insipidus, cerebellar syndromes, orbital lesions, and extra-axial masses involving the dura.     

Myoclonic epilepsy with ragged-red fibers (MERRF): an immunohistochemical study of the brain

Myoclonic epilepsy with ragged-red fibers (MERRF) is a maternally inherited disorder of oxidative phosphorylation due to specific point mutations within the mitochondrial tRNA(Lys) gene. Mitochondrial dysfunction in the central nervous system (CNS) of patients with MERRF accounts for the neurological manifestations of the disease. Antibodies against subunits of complex I, III, IV and V of the respiratory chain were used to study the expression of these proteins in the frontal cortex, cerebellum and medulla from an autoptic case of MERRF. We found a selective decreased expression of subunit II of cytochrome c oxidase (COX-II) in these regions. Immunohistochemical abnormalities were more widespread than the lesions described by traditional histopathological techniques and made possible an attempt of explanation for the neurological symptoms of the patient.     

Actinomycotic brain abscess

Actinomycosis is a chronic, suppurative and granulomatous bacterial infection, which tends to form abscesses. Involvement of the central nervous system (CNS) is rare. We describe the clinical and neuroradiological findings of four patients (3 men and one female) diagnosed of actinomycotic brain abscesses. Risk factors were dental pathology, intrauterine device use, alcohol abuse and Rendu-Osler-Weber disease. Clinical manifestations were those of a space-occupying lesion. CT scan findings were varied and little specific: hemispheric or periventricular location, pyocephalus, rim-enhancing and edema. MRI was superior in disclosing pyocephalus. Diagnosis was performed by microbiological and pathological findings. Despite surgery and antibiotics, two of the patients died. In conclusion, the infection of the CNS by Actinomyces is potentially fatal and should be considered in those patients with cerebral abscess.     

Retroperitoneal round-cell liposarcoma associated with paraneoplastic pemphigus presenting as lichen planus pemphigoides-like eruption

OBJECTIVE: To investigate the relationship between angiotensin-converting enzyme (ACE) gene insertion/deletion polymorphism and the clinico-pathological manifestations in patients with immunoglobulin nephropathy (IgAN). METHODS: A flanking primer pair and an insertion-specific primer pair were used to perform two polymerase chain reactions so as to analyse the insertion/deletion polymorphism of ACE gene. RESULTS: There was a significantly higher genotype frequency for DD genotype in IgAN patients. The frequencies for DD genotype were also higher in those patients with hypertension and/or heavy proteinuria and/or severe glomerular sclerosis (P < 0.05). CONCLUSIONS: We observed a significant association of the deletion polymorphism of ACE gene with renal insufficiency, hypertension and severe glomerular lesions at biopsy. The deletion allele may play a role, at least to some extent, in the deterioration and progression in IgA nephropathy.     

Mechanism of action of a new component of the Ca(2+)-dependent proteolytic system in rat brain: the calpain activator

OBJECTIVE: Using single photon emission computed tomography (SPECT) we evaluated the presence and evolution of changes in brain perfusion in juvenile systemic lupus erythematosus (JSLE). METHODS: SPECT was performed in 14 patients with active JSLE divided in 2 groups: the first included 7 patients without central nervous system (CNS) involvement and the second 7 patients with minor neuropsychiatric symptoms (headache, reactive depression, cognitive impairment, mood swing). SPECT findings were compared to seroimmunological and magnetic resonance imaging (MRI) data. After 6 month followup, a second SPECT scan was performed in 12 of 14 patients. RESULTS: At baseline, SPECT showed perfusion defects in 2 patients without neuropsychiatric symptoms and in 5 patients with CNS involvement. In one of the 7 patients with altered SPECT, MRI showed focal hyperintensities. MRI alterations were observed in another patient who had a normal SPECT scan. Cortical atrophy was present in 5 of 14 patients. Correlation between neuropsychiatric manifestations and SPECT findings was not clearly evident because the major part of JSLE patients with CNS involvement and with SPECT alterations had multiple symptoms, but showed focal hypoperfusion on SPECT imaging. No significant association was found between seroimmunological data and SPECT findings. At followup, improvement of perfusion alterations was observed in 6 of 7 patients with altered SPECT and, in 3 of them, findings might be attributed to changes in steroid treatment. CONCLUSION: Perfusion abnormalities in SLE may represent reversible lesions or subclinical CNS involvement. Moreover, SPECT imaging appears to be useful in detecting and monitoring CNS involvement in SLE.     

Hepatic veno-occlusive disease in a case of polymyositis associated with thrombotic thrombocytopenic purpura/hemolytic uremic syndrome

A 50-year-old woman was treated with prednisolone for polymyositis. During the therapy, thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) occurred. Neither plasma infusion nor plasma exchange could relieve the clinical manifestations of TTP/HUS. Moreover, massive ascites appeared and worsened her condition. She died approximately one year after the diagnosis of polymyositis. The autopsy revealed centri-lobular hepatic necrosis and nonthrombotic obliteration of hepatic small veins. The diagnosis of hepatic veno-occlusive disease (VOD) was made. It was suspected that common factors other than cytoreductive therapy had damaged the endothelium and caused TTP/HUS and VOD in a case of polymyositis.     

Lysozyme activity in cerebrospinal fluid. Studies in inflammatory and non-inflammatory CNS disorders

Lysozyme activity was measured in cerebrospinal fluid (CSF) from 114 patients with inflammatory (bacterial and serous meningitis, polyradiculitis, encephalitis) and non-inflammatory (multiple sclerosis, CNS tumors, cerebral vascular diseases) CNS diseases. Highly elevated values were found consistently in patients with bacterial meningitis. Elevated values were found also in patients with encephalitis, polyradiculitis, multiple sclerosis and CNS tumors, but a considerable overlapping between these groups and normal controls precludes the use of CSF lysozyme measurements as a diagnostic aid in the latter disease groups. Simultaneous measurements of lysozyme, albumin and IgG in CSF and serum suggested that the mechanism for increased CSF lysozyme values in bacterial meningitis is mainly a breakdown of the blood/brain barrier, whereas the increased CSF lysozyme values in the remaining groups of patients are more likely caused by production of lysozyme by cells within the meninges (neutrophilic granulocytes, monocytes?).     

Recurrence of haemolytic-uraemic syndrome in renal transplants: a single-centre report

BACKGROUND: The incidence of recurrence of haemolytic-uraemic syndrome (HUS) in renal allografts appears to vary by centre, with the highest rates reported from the University of Minnesota. It is possible that the high rate of HUS recurrence at this institution reflects a transplant population skewed towards patients with a form of HUS that is more likely to recur in the allograft. METHODS: This study examined whether the initial episode of HUS in the native kidneys was preceded by a diarrhoeal prodrome ('classical HUS') or not ('atypical HUS'), and evaluated transplant outcomes in 24 patients who received 36 transplants at the University of Minnesota between 31 May 1972 and 31 December 1994. RESULTS: Eighteen of the 24 patients had atypical HUS, three had classical HUS, and in three patients the presence or absence of a diarrhoeal prodrome could not be determined. Recurrent HUS, defined as microangiopathic haemolytic anaemia, thrombocytopenia, renal insufficiency, and allograft biopsy findings compatible with HUS, occurred 16 times in 14 grafts in 11 patients. Nine of these patients had atypical HUS, one had classical HUS, and in one the nature of the prodrome could not be determined. Eleven of the 14 initial recurrences took place within 2 months of transplant. Recurrence was not more frequent in patients who received cyclosporin or antilymphocyte preparations. Actuarial analysis using matched controls showed poorer graft survival in patients with a primary diagnosis of HUS (P = 0.007), due to the high frequency of graft loss in HUS patients with recurrence. CONCLUSION: Based upon these data and a review of the literature, it can be concluded that the risk of recurrence of HUS in the allograft is confined almost entirely to patients with atypical forms of HUS.     

A study for serodiagnosis of verotoxin-producing Escherichia coli (enterohemorrhagic E. coli) O157 by the bacterial agglutination technique

We evaluated the usefulness of bacterial agglutination antibodies for serodiagnosis of verotoxin-producing Escherichia coli (enterohemorrhagic E. coli) O157 infections. We examined 50 serum samples from 50 control children (whiout diarrhea 31, with diarrhea 19), 24 samples from 8 diarrhea cases due to O157:H7, 37 samples from 14 cases of hemolytic uremic syndrome (HUS) for antibodies to heat-killed E. coli E32511 (O157:H.-) strain using the bacterial agglutination technique. Of the control sera all but one (x80) showed 20 > or = in the antibody. All the diarrhea patients due to O157:H7 showed a significant rise (x160-x5120) of the titers in the sera at 5-7 days on illness, after that the titers fell rapidly. Significant antibody rise (x160-x5120) was detected in twelve out of 14 HUS patients at the early stage of the illness which fell in the convalescent phase. The assay appeared to be a useful serodiagnostic technique because of its easiness and simplicity as well as because of its high sensitivity and specificity.     

Physiological and pathological roles of interleukin-6 in the central nervous system

The cytokine interleukin-6 (IL-6) is an important mediator of inflammatory and immune responses in the periphery. IL-6 is produced in the periphery and acts systemically to induce growth and differentiation of cells in the immune and hematopoietic systems and to induce and coordinate the different elements of the acute-phase response. In addition to these peripheral actions, recent studies indicate that IL-6 is also produced within the central nervous system (CNS) and may play an important role in a variety of CNS functions such as cell-to-cell signaling, coordination of neuroimmune responses, protection of neurons from insult, as well as neuronal differentiation, growth and survival. IL-6 may also contribute to the etiology of neuropathological disorders. Elevated levels of IL-6 in the CNS are found in several neurological disorders including AIDS dementia complex, Alzheimer's disease, multiple sclerosis, systemic lupus erythematosus, CNS trauma, and viral and bacterial meningitis. Moreover, several studies have shown that chronic overexpression of IL-6 in transgenic mice can lead to significant neuroanatomical and neurophysiological changes in the CNS similar to that commonly observed in various neurological diseases. Thus, it appears that IL-6 may play a role in both physiological and pathophysiological processes in the CNS.     

N-3 and n-6 fatty acid metabolism in undifferentiated and differentiated human intestine cell line (Caco-2)

Antiphospholipid antibody is associated with a clinical syndrome of vascular thrombosis, thrombocytopenia, recurrent fetal loss and livedo reticularis, whether or not a clinical diagnosis of systemic lupus erythematosus (SLE) coexists. Central nervous system involvement in SLE is multifactorial, thrombotic events, antineuronal antibodies, hypertension, infection, side effects of drugs etc. Antiphospholipid antibodies may play a role in focal neurological manifestations in SLE. In the absence of SLE, different neurological symptoms are well associated with antiphospholipid antibodies including stroke, seizures, dementia, migraine, ocular ischemia, chorea, transverse myelopathy, cerebral phlebitis. Other association are more controversal like Guillain Barré syndrome, motor neuron disease, communicating hydrocephalus. In all patients with antiphospholipid antibodies with neurological involvement, cerebral MRI may be performed with an echocardiographic study because a possible association with Libman and Sacks endocarditis, valve dysfunction or cardiac thrombus source of cerebral ischemia.     

Effects of 5-HT1A receptor agonists on patterns of rat motor activity in relation to effects on forebrain monoamine synthesis

The majority of cases of hemolytic-uremic syndrome and a smaller proportion of cases of thrombotic thrombocytopenic purpura have recently been shown to result from a toxin produced by enteric bacteria, referred to as verotoxin, or Shiga-like toxin. The predominant toxin-producing bacterial strain in North America is E. coli O157:H7, which causes hemorrhagic colitis in humans after ingestion of contaminated meat. The toxin is believed to gain entry to the circulation from the bowel wall; it then binds to specific glycolipid receptors abundant on renal vascular endothelial cells. The toxin inactivates ribosomes inside the cells, thereby killing them and producing the clinical manifestations of hemolytic-uremic syndrome. Recognition of the etiology of hemolytic-uremic syndrome may lead to better prospects for prevention and treatment.     

Disorders of granulocytes induced by toxic agents

In 152 consecutively selected patients with detrusor hyperreflexia (DH) 96 (63 per cent) had neurological disorders. Thirty-two patients did not show any primary neurological or urological cause for DH. This group was chosen to elucidate the evaluation of possible neurological symptoms in relation to the urological symptomatology. Nine had died and one failed to appear to the neurological examination. Twelve (63 per cent) of the 22 examined patients showed signs of lesions in different parts of the central nervous system, particularly cerebrovascular diseases and myeloneuropathy. Six had had neurological symptoms for years. In two the urological symptoms were first to appear. In the group with no neurological complaints the urological symptoms had existed for 2-30 years. No essential difference was found in the degree of voiding disturbance whether or not neurological signs were disclosed. It is concluded that the discovery of DH should be followed by a neurological examination to disclose further signs of lesions in CNS. Likewise, an extended urological examination with demonstration of DH might help in the evaluation of an obscure neurological disease.     

Striving to prevent falls in an acute care setting--action to enhance quality

Endothelial damage is thought to be a contributing factor in the pathogenesis of Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndromes (TTP/HUS). The present studies measured two markers of endothelial cell stimulation and/or activation [von Willebrand Factor (vWF:Ag) and thrombomodulin (TM)] in patients with TTP/HUS disorders and compared them to controls. The patient groups consisted of adults with TTP/HUS, with (n = 13) and without (n = 14) peak Cr levels >2.0 mg/dl. Additionally, 52 patients with Bone Marrow Transplant-associated Thrombotic Microangiopathy (BMT-TM) following allogeneic BMT were evaluated. Both vWF:Ag and TM were elevated in all patient groups compared to controls. TTP/HUS patients with peak Cr >2.0 mg/dl had higher TM levels (P < 0.001) than did those with peak Cr levels below 2 mg/dl. However, thrombomodulin/ creatinine (TM/Cr) ratios did not differ in these two groups nor did they differ from controls. BMT-TM pts had higher vWF:Ag levels and higher TM/Cr ratios than controls and TTP/ HUS, P < 0.001. The median TM/Cr ratio in BMT-TM was 91 (range = 34-229) compared to 38 (range = 29-50) in controls, P < 0.001 and 38 (range = 6 to 156) in TTP/HUS, P < 0.001. Additionally both TM (P < 0.001) and TM/Cr (P < 0.02) were higher in patients with Grades 3 and 4 BMT-TM compared to those with Grade 2 BMT-TM. These results suggest that endothelial cell activation occurs in TTP/HUS and BMT-TM. Since TM/Cr ratios were higher in BMT-TM compared to TTP/HUS, these findings suggest that the mechanism of elevated TM in BMT-TM cannot be explained solely by altered renal excretion. Taken together, these findings strongly indicate a role of endothelial cell damage in BMT-TM.     

Human mucopolysaccharidosis IIID: clinical, biochemical, morphological and immunohistochemical characteristics

Mucopolysaccharidosis IIID (MPS IIID) is one of the rarest of the MPS-III syndromes. To date, the clinical manifestations of 10 patients have been reported, the deficient N-acetylglucosamine 6-sulfatase (G6S) enzyme has been purified, and the G6S gene has been cloned, sequenced and localized. However, morphological manifestations of this condition have not been reported and the pathogenesis of the severe neurological deficits remains an enigma. In this paper we describe and correlate the clinical, biochemical and pathological observations for 2 cases of MPS IIID. We used monoclonal antibodies against heparan sulfate (HS) and GM2-ganglioside, thin layer chromatography, mass spectrometry, and morphological techniques to demonstrate the nature and the distribution of the uncatabolized substrates. The majority of the cells in various tissues showed morphological changes expected with lysosomal storage of HS. The central nervous system (CNS) was most severely affected because of the secondary storage of GM2 and GM3 gangliosides in addition to the primary accumulation of HS. The extent as well as the distribution of the diverse storage materials varied within and among different neurons as observed in MPS-III A, B, and C syndromes. This study supports the hypothesis that the neurological dysfunction and neurodegeneration common to the Sanfilippo syndromes is, in part, due to the secondary metabolic perturbations induced by HS accumulation.