Integrin alpha4beta1 (VLA-4) expression and activity in retinal and peripheral neurons

The integrin alpha4beta1 fulfills important roles in inflammation and hematopoesis, but its functions in neurons are not well understood. Here we show that the alpha4 subunit is expressed on mouse retinal ganglion cells (RGCs) and undifferentiated retinal neuroblasts during the period of axon extension and migration. To determine if alpha4 integrins expressed by retinal neurons were active, neurons were cultured on known alpha4 ligands in vitro. Recombinant soluble vascular cell adhesion molecule 1 (rsVCAM-1), fibronectin, and osteopontin (OPN) induced neurite outgrowth that was diminished by function blocking antibodies specific for alpha4. Neurite outgrowth on OPN was also blocked by antibodies to the integrin beta1 subunit, implicating the alpha4beta1 heterodimer as one integrin receptor mediating outgrowth on OPN. OPN immunoreactivity was detected in the RGC fiber layer and optic nerve, suggesting that it may act as an alpha4 ligand in vivo. Neurons from chick lumbar sympathetic ganglia, chick dorsal root ganglia, and mouse superior cervical ganglia also extended neurites on rsVCAM-1, suggesting that integrin alpha4beta1 may play a role in the development of multiple neuronal cell types.     

Microscopic pulmonary embolisation of an indwelling central venous catheter with granulomatous inflammatory response.

Indwelling catheters can disintegrate into tiny fragments and embolise. Once the fragments are detected radiographically, they can be removed using vascular intervention techniques. Rarely, indwelling catheters dwindle into inextricable pieces that embolise into minute pulmonary vessels and lymphatics, causing granulomatous changes microscopically. The present study reports a 54-yr-old female who had received several indwelling central lines during several abdominal surgeries over a 5-yr period. The patient developed a noncaseating granulomatous skin lesion followed by exertional dyspnoea a few months later. Chest radiographs and computed tomography showed diffuse interstitial infiltrates. Open lung biopsy showed two types of granulomas: 1) peri-lymphangitic and peri-bronchiolar non-necrotising granulomas consistent with sarcoidosis; and 2) distinct foreign body granulomas. In some of the foreign body granulomas, confocal Raman spectroscopy identified the presence of bisphenol-A-polycarbonate, a polymer commonly used in biomedical devices. The patient improved following treatment with prednisone followed by methotrexate. The present case illustrates an interesting combination of two causes of granulomatous disease, the importance of examining all biopsy specimens from sarcoidosis patients for foreign particles and the rare occurrence of microscopic embolisation of catheter fragments to the lung with foreign-body giant cell reaction to them.     

Nodular regenerative hyperplasia of the liver in children

Sixteen cases of nodular regenerative hyperplasia of the liver in children are presented. The patients, 10 girls and 6 boys, were between the ages of 7 months and 13 years, with a median of 6 years. Clinically, nine children presented with hepatomegaly or splenomegaly, with and without signs of portal hypertension. A history of anticonvulsant drug therapy was obtained in four patients. Associated conditions in the remaining three cases were Donohue's syndrome, disseminated intravascular coagulation, and angiomyolipoma of the kidney. In five patients a clinical diagnosis of primary intra-abdominal tumor was made. Follow-up showed that six patients died of causes unrelated to the nodular hyperplasia. Two patients were asymptomatic when last seen 5 and 18 years after the initial diagnosis of nodular hyperplasia. Both patients underwent shunt surgery. No follow-up was available for eight patients. The importance of recognizing this entity in the pediatric age group, as well as its histopathologic differential diagnosis, is stressed.     

Characterization of human immunodeficiency virus (HIV1C) variants in peripheral blood mononuclear cells and spermatozoa

The presence of distinct viral variants in different cells and secretions of the same person influences the transmission of HIV as well as the response to the host defense and to therapy. Sperm-associated virus is also a risk factor for sexual transmission of HIV. Characterization of the C2-V3 region of HIV1C env gene by the Heteroduplex Mobility Assay (HMA) and sequencing demonstrated the presence of distinct variants in the peripheral blood mononuclear cells (PBMCs) and the sperm of the same individual (n = 6). The translated amino acid sequences of HIV variants in the PBMCs of all the study participants (n = 12) and spermatozoa of the six participants characterized showed the presence of distinct variants with different numbers of N-linked glycosylation (NLG) sites. Infectivity of PBMCs of these persons by co-culture with PBMCs from healthy individuals as detected by the p24 levels in the culture supernatant did not show a correlation with the blood plasma viral load. Interestingly, the infectivity of the sperm samples from four of the five individuals showed positive correlation with the viral load in seminal plasma. The study suggests the presence of distinct viral variants in the sperm and PBMCs of the same person with differential infectivity, and the NLG sites may be associated with the affinity of HIV to receptor/co-receptor usages as well as affinity toward neutralizing antibodies which may influence the risk of sperm associated virus in sexual transmission of HIV and transmit the virus further to distal cells.     

Metals and health: a clinical toxicological perspective on tungsten and review of the literature

Tungsten and tungsten compounds are considered toxicologically relatively safe. Concern regarding the potential health and environmental effects of depleted uranium and lead in military applications has lead many countries to explore the possibility of applying toxicologically safer metals. Heavy metal tungsten alloy-based munitions have been therefore introduced as a replacement in munitions and as kinetic energy penetrators. Although the toxicological profiles of all these metals are well known, their internalization as embedded shrapnel may be considered a new route for long-term exposure. Studies in experimental animals and cell culture indicate that pellets based on heavy metal tungsten alloy possess carcinogenic potential previously unseen for depleted uranium and/or lead. Other metals in the tungsten alloy such as nickel or cobalt may contribute to such a risk. Accordingly, the long-term tungsten-related health risk is reason for concern. This article reviews toxicological and clinical literature and provides new perspectives on tungsten and tungsten-based alloys.     

Efficacy of Duloxetine in Patients with Chronic Pain Conditions

The primary objective of this study is to review the efficacy of duloxetine in treating chronic pain using the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) recommendations for clinical significance across chronic pain states. These include pain intensity, patient ratings of overall improvement, physical functioning, and mental functioning. This review comprised the side-by-side analyses of 12 double-blind, placebo-controlled trials of duloxetine in patients with chronic pain (diabetic peripheral neuropathic pain, fibromyalgia, chronic pain due to osteoarthritis, and chronic low back pain). Patients received duloxetine (60 to 120 mg/day) or placebo. Average pain reduction was assessed over 3 months as the primary efficacy outcome. Other measures used were physical function and Patient Global Impression of Improvement. In 10 of the 12 studies, statistically significant greater pain reduction was observed for duloxetine- compared with placebo-treated patients. The response rates based on average pain reduction, improvement of physical function, and global impression were comparable across all 4 chronic pain states. Compared with patients on placebo, significantly more patients treated with duloxetine reported a moderately important pain reduction (≥30% reduction) in 9 of the 12 studies, a minimally important improvement in physical function in 8 of the 12 studies, and a moderately important to substantial improvement in Patient Global Impression of Improvement rating in 11 of the 12 studies. The analyses reported here show that duloxetine is efficacious in treating chronic pain as demonstrated by significant improvement in pain intensity, physical functioning, and patient ratings of overall improvement.     

Ocular manifestations of tubercular meningitis: a clinico-biochemical study

Forty-eight children with tubercular meningitis were observed and followed up for development of ocular sequelae over a period of four months. Commonest ocular abnormality encountered in this condition was optic disc change (62%) of which papillitis was the most frequent. The incidence of pupillary change and cranial nerve paralysis was seen to be 48% and 28% respectively. Anisocoria and mydriasis were commonly observed pupillary changes. The third cranial nerve was the most frequent nerve involved in this condition. It was observed that patients who had high CSF protein content (greater than 75 mg%) showed more chances of development of primary optic atrophy (P value 0.001). Choroidal tubercle and papilledema were found to be signs of grave prognostic significance.     

Comparison of the efficacy of intrauterine diclofenac and ibuprofen pellets as adjuvants to quinacrine nonsurgical female sterilization

To investigate relative efficacy of intrauterine diclofenac and ibuprofen as adjuvants to intrauterine quinacrine for nonsurgical sterilization, a total of 900 women were systematically allocated to 2 monthly insertions of pellets of diclofenac (75 mg) or ibuprofen (55.5 mg) as adjuvants to intrauterine quinacrine (216 mg) in a rural private practice in West Bengal, India. All women were prescribed oral contraceptives for three month from first insertion. In the middle of the study increased care was taken to insert pellets at the fundus. There was no statistically significant difference found in cumulative life-table pregnancy failure rates at 36 months for women receiving diclofenac (2.7±0.82) or ibuprofen (3.4±0.89). Taking care to insert pellets at the fundus resulted in a decline of failures at 24 months from 4.4±0.92 to zero. Intrauterine administration of pellets of quinacrine (216 mg) plus diclofenac (75 mg) or ibuprofen (55.5 mg) with 3 months' oral contraception provides acceptable efficacy if pellets are inserted to the fundus.

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Resumen A fin de investigar la eficacia relativa de diclofenac e ibuprofen intrauterinos como adyuvantes de la quinacrina uterina para la esterilización no quirúrgica, se asignó sistemáticamenete un total de 900 mujeres a 2 inserciones mensuales de bolitas de 75 mg de diclofenac o de 55,5 mg de ibuprofen como adyuvantes de 216 mg de quinacrina intrauterina en un consultorio rural privado de Bengala Occidental, India. A todas las mujeres se les recetaron anticonceptivos orales durante tres meses desde la primera inserción. A mediados del estudio se prestó especial atención a la inserción de las bolitas en el fondo. No se determinó ninguna diferencia estadísticamente significativa en las tasas de fallo de las tablas de vida acumulativas a los 36 meses en el caso de las mujeres a las que se había recetado diclofenac (2,7±0,82) o ibuprofen (3,4±0,89). El cuidado en la inseción de las bolitas en el fondo originó una disminució de los fallos a los 24 meses, de 4,4±0,92 a cero. La administración intrauterina de bolitas de 216 mg de quinacrina más 75 mg de diclofenac o 55,5 mg de ibuprofen con 3 meses de anticonceptivos orales proporciona una eficacia aceptable si las bolitas se insertan en el fondo.

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Resumé Lors d'une étude conduite dans le cabinet médical dune zone rurale au Bengale occidental (Inde) en vue de déterminer l'utilité relative du diclofénac et de l'ibuprofen en tant qu'adjuvants à la quinacrine, tous administrés par voie intrautérine pour la stérilisation non chirurgicale, on a pratiqué sur un total de 900 femmes, à 1 mois d'intervalle, 2 insertions de pellets contenant soit 75 mg de diclofénac soit 55,5 mg d'ibuprofen en tant qu'adjuvants à 216 mg de quinacrine. Des contraceptifs oraux ont été prescrits à toutes les femmes pendant les trois mois qui ont suivi la première insertion. Au milieu de la période d'étude, on a veilé plus particulièrement à insérer les pellets au fond de la cavité. On n'a constaté aucune différence statistiquement significantive dans les taux d'échec par grossesse sur les tables de survie cumulées à 36 mois, que les femmes aint recu du diclofénac (2,7±0,82) ou de l'ibuprofen (3,4±0,89). En prenant soin d'insérer les pellets au fond de la cavité, il a été possible de ramener le taux d'échecs à 24 mois de 4,4±0,92 à zéro. L'administration par voie intrautérine de pellets de 216 mg de quinacrine, plus 75 mg de diclofénac ou 55,5 mg d'ibuprofen, accompagnée d'une contraception orale pendant 3 mois est d'une utilité acceptable si les comprimés sont insérés au fond de la cavité.