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Chagas disease is a tropical disease caused by the protozoan parasite Trypanosoma cruzi and currently affects millions of people worldwide. Curcumin (CUR), the major constituent of turmeric spice (dry powder of Curcuma longa L. plant rhizomes and roots), exhibits antiparasitic activity against protozoan parasites in vitro. However, because of its chemical instability, poor cellular uptake and limited bioavailability it is not suitable for clinical use. The objective of this study was to synthesize and evaluate in vitro CUR monoketone analog dibenzalacetone (DBA 1) and its non-phenolic, methoxy (2-4) and chloro (5) derivatives for better stability and bioavailability against T. cruzi. Diveratralacetone, the tetramethoxy DBA (DBA 3), was found to be the CUR analog with most enhanced activity against the amastigote forms of four strains of T. cruzi tested (Brazil, CA-I/72, Sylvio X10/4 and Sylvio X10/7) with 50% inhibitory concentration (IC50) < 10 µM (1.51-9.63 µM) and selectivity index (SI) > 10 (C2C12 non-infected mammalian cells). This was supplemented by time-course assessment of its anti-T. cruzi activity. DBA 1 and its dimethoxy (DBA 2) and hexamethoxy (DBA 4) derivatives were substantially less active. The inactivity of dichloro-DBA (DBA 5) was indicative of the important role played by oxygenated groups such as methoxy in the terminal aromatic rings in the DBA molecule, particularly at para position to form reactive oxygen species essential for anti-T. cruzi activity. Although the DBAs and CUR were toxic to infected mammalian cells in vitro, in a mouse model, both DBA 3 and CUR did not exhibit acute toxicity or mortality. These results justify further optimization and in vivo anti-T. cruzi activity evaluation of the inexpensive diveratralacetone for its potential use in treating Chagas disease, a neglected parasitic disease in economically challenged tropical countries.

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ZTI-01 (fosfomycin for injection) is a broad-spectrum antibiotic with a novel mechanism of action and is currently under development in the United States for treatment of complicated urinary tract infections. Globally, fosfomycin and polymyxin B are increasingly being used to treat multidrug-resistant Gram-negative infections. The objectives were to evaluate the pharmacodynamic activity of polymyxin B and fosfomycin alone and in combination against KPC-producing Klebsiella pneumoniae and to assess the rate and extent of emergence of resistance to different antibiotic regimens. Two clinical isolates, BRKP26 (MIC of polymyxin B[MICPMB], 0.5 mg/liter; MIC of fosfomycin [MICFOF], 32 mg/liter) and BRKP67 (MICPMB, 8 mg/liter; MICFOF, 32 mg/liter) at an initial inoculum of 107 CFU/ml, were evaluated over 168 h in a hollow-fiber infection model simulating clinically relevant polymyxin B (2.5-mg/kg loading dose as a 2 h-infusion followed by 1.5-mg/kg dose every 12 h [q12h] as a 1-h infusion) and fosfomycin (6 g q6h as a 1-h or 3-h infusion) regimens alone and in combination. Population analysis profiles (PAPs) and MIC testing were performed to assess emergence of resistance...

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The effects of interleukin-10 (IL-10) and glucose on mRNA and protein expression of osteoprotegerin (OPG), and its ligand, receptor activator of nuclear factor-κB ligand (RANKL), were investigated in human periodontal ligament fibroblasts (HPDLFs). Primary HPDLFs were treated with different concentrations of IL-10 (0, 1, 10, 25, 50, and 100 ng/mL) or glucose (0, 5.5, 10, 20, 30, and 40 mmol/L). Changes in mRNA and protein expression were examined using the reverse-transcription polymerase chain reaction (RT-PCR) and Western blot analysis, respectively. After IL-10 treatment, mRNA and protein levels of OPG were increased, while mRNA and protein levels of RANKL were decreased (P<0.05), both in a concentration-dependent manner. Glucose stimulation had the opposite concentration-dependent effect to that of IL-10 on OPG and RANKL expression. IL-10 upregulated OPG expression and downregulated RANKL expression, whereas high glucose upregulated RANKL and downregulated OPG in HDPLFs. Abnormal levels of IL-10 and glucose may contribute to the pathogenesis of periodontal disease.

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The effects of interleukin-10 (IL-10) and glucose on mRNA and protein expression of osteoprotegerin (OPG), and its ligand, receptor activator of nuclear factor-κB ligand (RANKL), were investigated in human periodontal ligament fibroblasts (HPDLFs). Primary HPDLFs were treated with different concentrations of IL-10 (0, 1, 10, 25, 50, and 100 ng/mL) or glucose (0, 5.5, 10, 20, 30, and 40 mmol/L). Changes in mRNA and protein expression were examined using the reverse-transcription polymerase chain reaction (RT-PCR) and Western blot analysis, respectively. After IL-10 treatment, mRNA and protein levels of OPG were increased, while mRNA and protein levels of RANKL were decreased (P<0.05), both in a concentration-dependent manner. Glucose stimulation had the opposite concentration-dependent effect to that of IL-10 on OPG and RANKL expression. IL-10 upregulated OPG expression and downregulated RANKL expression, whereas high glucose upregulated RANKL and downregulated OPG in HDPLFs. Abnormal levels of IL-10 and glucose may contribute to the pathogenesis of periodontal disease.

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Klippel-Trenaunay syndrome (KTS) is a rare congenital, vascular disorder affecting one or more limbs. The syndrome is characterized by capillary malformations, soft tissue or bony hypertrophy and varicose veins or venous malformations. We present a case of this disorder in a twelveyear old boy who had an enlarged right lower limb with varicosities. Investigations revealed extensive superficial and deep venous varices, with dilatation of the right common iliac and external iliac veins. Klippel-Trenaunay syndrome should be suspected in a child presenting with capillary haemangioma and an enlarged limb.

El síndrome de Klippel-Trenaunay (KTS) es un raro trastorno congénito vascular que afecta a una o más extremidades. El síndrome se caracteriza por malformaciones capilares, hipertrofia ósea o del tejido suave, y várices o malformaciones venosas. Presentamos un caso de este trastorno en un muchacho de doce años que tenía una extremidad inferior derecha agrandada con varicocidades. Las investigaciones revelaron varices superficiales y várices venosas profundas, con dilatación de las venas ilíacas comunes derecha y las venas ilíacas externas. El síndrome de Klippel-Trenaunay se debe sospechar en un niño que se presenta con hemangioma capilar y agrandamiento de un miembro.

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Klippel-Trenaunay syndrome (KTS) is a rare congenital, vascular disorder affecting one or more limbs. The syndrome is characterized by capillary malformations, soft tissue or bony hypertrophy and varicose veins or venous malformations. We present a case of this disorder in a twelve-year old boy who had an enlarged right lower limb with varicosities. Investigations revealed extensive superficial and deep venous varices, with dilatation of the right common iliac and external iliac veins. Klippel-Trenaunay syndrome should be suspected in a child presenting with capillary haemangioma and an enlarged limb.

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Aim: To describe ocular manifestations in newly diagnosed borderline lepromatous (BL) and lepromatous leprosy (LL) patients in India. METHODS: Ocular complications, at enrolment, occurring in all new borderline lepromatous and lepromatous leprosy patients detected by active case finding within the geographically defined leprosy endemic area of the Gudiyattam Taluk in India from 1991 to 1997 who consented to ocular examinations every 6 months, during and 5 years after treatment with multidrug therapy (MDT), were studied. RESULTS: Orbicularis oculi weakness (4.62 per cent), lagophthalmos (4.20 per cent), ectropion (0.42 per cent), trichiasis (0.84 per cent), blocked nasolacrimal ducts (1.68 per cent), pterygium (11.34 per cent), impaired corneal sensation (53 per cent), corneal opacity (10.5 per cent), corneal nerve beading (1.68 per cent), punctate keratitis (1.26 per cent), keratic precipitates (4.62 per cent), iris atrophy (1.68 per cent), and cataract (12.6 per cent) were ocular complications seen in the 301 lepromatous patients at enrolment. 4.6 per cent had blind eyes. Increasing age was associated with ocular complications. 80 per cent of patients were skin smear acid fast bacilli (AFB) positive. The LL/BL ratio was 1:6.4. 71 per cent had some limb deformity. 44 per cent had only leprosy related ocular complications (LROC), 28 per cent had only general ocular complications (GOC) while 14 per cent had both LROC and GOC. Ocular complications were significantly related to leg deformities. Corneal nerve beading was seen most in LL patients (100 per cent) having high bacterial content. Lagophthalmos and muscle weakness were associated with reversal reactions. CONCLUSIONS: Corneal nerve beading occurs in LL patients with high bacillary count. Patients with reversal reaction are more likely to present with orbicularis oculi weakness and lagophthalmos. Leprosy related ocular complications and general ocular complications are significant problems in newly diagnosed lepromatous patients. Elderly, deformed, skin smear positive, lepromatous patients are associated with increased ocular morbidity and form a group that require acceptable and accessible eye care.

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Neuropathologic and neurochemical correlates of psychosis were determined using brain tissue from 27 autopsy-confirmed cases of Alzheimer's disease. The densities of senile plaques and neurofibrillary tangles were determined in the middle frontal and superior temporal cortex, the prosubiculum, and the entorhinal cortex of the hippocampus. The concentrations of norepinephrine, dopamine, and serotonin, the metabolites of these biogenic amines, and the specific activity of choline acetyltransferase were also determined in these four cortical regions as well as in the substantia nigra, thalamus, amygdala, and caudate nucleus. Psychosis was associated with significantly increased densities of senile plaques and neurofibrillary tangles in the prosubiculum and middle frontal cortex, respectively, with trends toward increased densities of these lesions in the other areas examined. This finding is consistent with the increased rate of cognitive decline that accompanies this behavioral disorder. Psychosis was also associated with the relative preservation of norepinephrine in the substantia nigra, with trends in this direction for five of the remaining seven brain regions examined, and a significant reduction of serotonin in the prosubiculum that was accompanied by trends toward reduced levels of serotonin and 5 hydroxyindoleacetic acid in the remaining regions. The profile of neuropathologic and neurochemical changes associated with psychosis is distinct from that previously reported for major depression in the context of primary dementia.

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Five types of oculocutaneous albinism and two types of ocular albinism were found among 349 Puerto Rican albinos. The most prevalent type of albinism was the Hermansky-Pudlak syndrome (HPS). HPS was observed in five of every six albinos in Puerto Rico. The prevalence of HPS was highest in the northwestern quarter of the island, affecting approximately one in 1,800 persons, and approximately one in 22 are carriers of the gene. HPS is an autosomal recessively inherited triad of a tyrosinase-positive type of albinism, a hemorrhagic diathesis due to storage pool deficient platelets and accumulation of ceroid in tissues. The pigmentary phenotype of HPS albinos resembled that of any other type of oculocutaneous or ocular albinism. The most reliable method of diagnosing HPS is by a deficiency of platelet dense bodies observed by electron microscopy. The accumulation of ceroid in the tissues is associated with fibrotic restrictive lung disease and granulomatous enteropathic disease. The enteropathic disorder resembles Crohn's disease and with few exceptions, had its onset after 13 years of age. The major causes of death were fibrotic restrictive pulmonary disease, hemorrhagic episodes and sequelae of granulomatous enteropathic disease. Menometrorrhagia was common in women with HPS. No immune deficiency was found in HPS patients. The majority of patients with HPS had visual acuities of 20/200 or worse and consequently were legally blind. Albinos of all types, including HPS, lacked binocular vision due to nearly complete crossing of the optic tracts.

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The specific activity of antimycin A-insensitive nicotinamide adenine dinucleotide (NADH)-dependent cytochrome C reductase, an enzyme associated with endoplasmic reticulum, was determined in the superior temporal, entorhinal, and cerebellar cortex of 16 patients who died with Alzheimer's disease and eight nondemented controls. The specific activity of choline acetyltransferase was also measured to provide an index of presynaptic cholinergic dysfunction. Our results revealed reciprocal changes in these activities that were of similar magnitude across the three regions examined. Furthermore, cytochrome C reductase activity was positively correlated with the density of neurofibrillary tangles, especially in the superior temporal cortex. These results support the hypothesis that Alzheimer's disease may be associated with an alteration of endoplasmic reticulum and the functions related to this intracellular membrane system, including the post-translational modification and localization of essential proteins.

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The extent of left-right asymmetry in the densities of senile plaques and neurofibrillary tangles and the levels of the cholinergic enzymes choline acetyltransferase and acetylcholinesterase were quantified in the middle frontal and superior temporal cerebral cortex, entorhinal cortex, and prosubiculum of the hippocampus from 21 patients who died with Alzheimer's disease. Morphologic lesions were more asymmetrically distributed than deficits in the cholinergic enzymes. Neither cerebral hemisphere showed consistently higher densities of senile plaques and neurofibrillary tangles, or lower levels of choline acetyltransferase and acetylcholinesterase. Deficits in the cholinergic enzymes tended to colateralize, while asymmetries of senile plaques and neurofibrillary tangles did not. Finally, left-right asymmetry in the density of senile plaques diminished with increasing neuropathologic severity, while similar evidence for diminishing left-right asymmetry of neurofibrillary tangle density or cholinergic enzyme activity with increasing severity was not found.

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Senile plaques (SPs), especially, and neurofibrillary tangles are important pathologic markers for the diagnosis of Alzheimer's disease (AD), but neither is pathognomonic for AD. We hypothesize that elevations in levels of phosphomonoesters, precursors of membrane phospholipids, occur early in the pathogenesis of AD and precede the appearance of SPs. In contrast, elevations in levels of phosphodiesters, breakdown products of phospholipids, reflect degeneration of neural membranes and will correlate with the appearance of SPs. Correlative phosphorus-31 magnetic resonance spectroscopy and morphologic studies conducted to test this hypothesis disclosed that elevations in levels of phosphomonoesters had a negative correlation with the numbers of SPs, and elevations in levels of phosphodiesters had a positive correlation with the numbers of SPs. No correlations were observed for either membrane parameter and neurofibrillary tangles. These findings support our hypothesis and suggest that aberrations in the synthesis of membrane phospholipids are early metabolic events in the pathogenesis of AD.

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