Diabetic peripheral neuropathy in people with type 2 diabetes: too little too late.

Diabetic peripheral neuropathy in people with type 2 diabetes is poorly managed because of its insidious onset, delayed diagnosis and more complex aetiology resulting from the contribution of not only hyperglycaemia, but also ageing, hyperlipidaemia, hypertension and obesity. Because there is no US Food and Drug Adminstration-approved disease-modifying therapy for diabetic peripheral neuropathy, the key to ameliorating it in type 2 diabetes has to be through earlier diagnosis and timely multi-factorial risk factor reduction. The management of painful diabetic peripheral neuropathy also requires a detailed appraisal of the choice of therapy, taking into account efficacy, patient wishes, comorbidities, side effect profile and potential for abuse.

Efficiency of random search with space-dependent diffusivity.

We address the problem of random search for a target in an environment with a space-dependent diffusion coefficient D(x). Considering a general form of the diffusion differential operator that includes Itô, Stratonovich, and Hänggi-Klimontovich interpretations of the associated stochastic process, we obtain and analyze the first-passage-time distribution and use it to compute the search efficiency E=〈1/t〉. For the paradigmatic power-law diffusion coefficient D(x)=D_{0}|x|^{α}, where x is the distance from the target and α<2, we show the impact of the different interpretations. For the Stratonovich framework, we obtain a closed-form expression for E, valid for arbitrary diffusion coefficient D(x). This result depends only on the distribution of diffusivity values and not on its spatial organization. Furthermore, the analytical expression predicts that a heterogeneous diffusivity profile leads to a lower efficiency than the homogeneous one with the same average level within the space between the target and the searcher initial position, but this efficiency can be exceeded for other interpretations.

Unitary evolution for a two-level quantum system in fractional-time scenario.

The time-evolution operator obtained from the fractional-time Schrödinger equation (FTSE) is said to be nonunitary since it does not preserve the norm of the vector state in time. As done in the time-dependent non-Hermitian quantum formalism, for a traceless non-Hermitian two-level quantum system, we demonstrate that it is possible to map the nonunitary time-evolution operator in a unitary one. It is done by considering a dynamical Hilbert space with a time-dependent metric operator, constructed from a Hermitian time-dependent Dyson map, in respect to which the system evolves in a unitary way, and the standard quantum mechanics interpretation can be made properly. To elucidate our approach, we consider three examples of Hamiltonian operators and their corresponding unitary dynamics obtained from the solutions of FTSE, and the respective Dyson maps.

Pattern formation in nanoporous titania templates.

We have carried out a systematic investigation into the formation of nanoscaled patterns in titania (TiO2) templates under dc anodization of Ti in HF acid. At lower acid concentrations (around 0.5 wt% HF) either pores or tubes form at the surface of anodized titanium foil. The pores or nanotubes are separated from the bottom Ti layer by a thin barrier layer of TiO2. The critical voltage where the transition from pores to tubes occurs has been determined. It is observed that the transition voltage shift towards higher voltages as acid concentration is increased, with pore formation disappearing altogether at high acid concentrations. We have also carried out a systematic investigation into the dependence of pore and tube parameters on the applied dc anodization voltage. Our results indicate that the barrier layer thickness, pore and tube length increase as a function of applied voltage.

A small subunit processome protein promotes cancer by altering translation.

Dysregulation of ribosome biogenesis or translation can promote cancer, but the underlying mechanisms remain unclear. UTP18 is a component of the small subunit processome, a nucleolar multi-protein complex whose only known function is to cleave pre-ribosomal RNA to yield the 18S ribosomal RNA component of 40S ribosomal subunits. Here, we show that UTP18 also alters translation to promote stress resistance and growth, and that UTP18 is frequently gained and overexpressed in cancer. We observed that UTP18 localizes to the cytoplasm in a subset of cells, and that serum withdrawal increases cytoplasmic UTP18 localization. Cytoplasmic UTP18 associates with the translation complex and Hsp90 to upregulate the translation of IRES-containing transcripts such as HIF1a, Myc and VEGF, thereby inducing stress resistance. Hsp90 inhibition decreases cytoplasmic UTP18 and UTP18-induced increases in translation. Importantly, elevated UTP18 expression correlates with increased aggressiveness and decreased survival in numerous cancers. Enforced UTP18 overexpression promotes transformation and tumorigenesis, whereas UTP18 knockdown inhibits these processes. This stress adaptation mechanism is thus co-opted for growth by cancers, and its inhibition may represent a promising new therapeutic target.

Inhibition of lung metastasis in mice induced by B16F10 melanoma cells by polyphenolic compounds.

Several polyphenolic compounds were tested for the inhibition of lung metastasis induced by B16F10 melanoma cells in mice. Oral administration of polyphenols such as curcumin and catechin at concentrations of 200 nmol/kg body weight were found to inhibit the lung metastasis maximally as seen by the reduction in the number of lung tumor nodules (80%). Other polyphenols which inhibited the lung tumor nodule formation were rutin (71.2%), epicatechin (61%), naringin (27.2%) and naringenin (26.1%). The polyphenols which did not inhibit lung tumor nodule formation were quercetin, morin and ellagic acid. Consequent to the inhibition of the lung tumor nodules, the life span of animals treated with polyphenols was also found to be increased. Curcumin (143.85%), catechin (80.81%) and rutin (63.59%) had maximal increase in life span. The results indicate a possible use of these compounds in arresting the metastatic growth of tumor cells.

Anti-metastatic activity of curcumin and catechin.

The inhibitory effects of curcumin and catechin on lung metastasis induced by B16F-10 melanoma cells were studied in female C57BL/6 mice. Curcumin and catechin significantly (P < 0.001) inhibited lung tumour formation (89.3% and 82.2%, respectively) and significantly increased the life span (143.9% and 80.8%, respectively). Moreover, lung collagen hydroxyproline and serum sialic acid levels were found to be significantly (P < 0.001) lower in treated animals compared to the untreated controls. Curcumin and catechin treatment (10 microg/ml) significantly inhibited the invasion of B16F-10 melanoma cells across the collagen matrix of the Boyden chamber. Gelatin zymographic analysis of the trypsin-activated B16F-10 melanoma cells sonicate revealed that curcumin- and catechin-treated zymograms did not show any metalloproteinase activity. Curcumin and catechin treatment did not inhibit the motility of B16F-10 melanoma cells across a polycarbonate filter in vitro. These findings suggest that curcumin and catechin inhibit the invasion of B16F-10 melanoma cells by inhibition of metalloproteinases, thereby inhibiting lung metastasis.

Magnetic and structural properties of electrochemically self-assembled Fe1-xCox nanowires.

Fe1-xCox (0 < or = x < or = 1) nanowires have been self-assembled by electrodeposition in porous alumina films. The crystal structure is bee at the Fe end. With increased addition of Co, the crystal structure remains bcc until about 67% addition of Co. At the Co end, the structure is a mixture of hcp and fcc. Magnetic studies show very high coercivities for the Fe-Co alloys in the bcc phase. For Fe0.67Co0.33 nanowires of diameter 9 nm, the coercivity is about 2900 Oe, whereas for Fe0.33Co0.67 nanowires, it is about 2850 Oe. Temperature and size dependence of magnetic properties show no indication of superparamagnetic effects down to wire diameters of 9 nm.

Effect of rasayanas in the inhibition of lung metastasis induced by B16F-10 melanoma cells.

Five rasayanas and one of the ingredients Emblica officinalis (EO), were studied for their antimetastatic activity using B16F-10 melanoma cells in C57BL/6 mice. Simultaneous oral administration (50 mg/animal/dose) of Brahma Rasayana (BR) and Aswagandha Rasayana (AR) significantly reduced the lung tumour nodule formation by 71.28% (P < 0.001) and 55.6% (P < 0.001), respectively. Similarly, the lung collagen hydroxyproline content and the serum sialic acid levels were also low in BR treated (4.8 +/- 0.97 ug/m protein; 35.6 +/- 2.6 ug/ml serum) and AR treated animals (6.15 +/- 0.5 ug/mg protein; 56.3 +/- 8.7 ug/ml serum) compared to the untreated controls (10.43 +/- 0.7 ug/mg protein; 161.3 +/- 9.5 ug/ml serum). Narasimha Rasayana (NR), Amrithaprasam (AP), Chyavanaprasam (CP) and Emblica extract (EO) administration had no significant effect in the reduction of lung nodule formation and lung hydroxyproline and serum sialic acid contents which was similar to that of untreated controls. Life span of BR, AR and NR treated animals was found to be significantly increased. These results indicate that BR and AR possess antimetastatic activity against melanoma cells.

Effect of Caffeine, a xanthine derivative, in the inhibition of experimental lung metastasis induced by B16F10 melanoma cells.

Caffeine, a methyl xanthine derivative, was studied to assess the effect on B16F10 melanoma induced experimental metastasis. Caffeine was administered at a dose of 100 and 50 mg/kg body weight by both routes, to tumour bearing animals. Solid tumour reduction studies with Caffeine showed a significant reduction in tumour volume for 100 mg/kg dose by both oral and i.p. routes. The Caffeine treated metastatic tumour bearing animals significantly (p<0.001) inhibited lung tumour nodules. Serum sialic acid levels and lung hydroxyproline contents in the treated groups were significantly (p<0.001) low, when compared with the untreated control animals. In the present study, our results suggest that Caffeine inhibits solid tumour development and pulmonary experimental metastasis induced by B16F10 melanoma cells, in murine model.

Pneumocystis carinii pneumonia in human immunodeficiency virus infected patients in Bombay: diagnosed by bronchoalveolar lavage cytology and transbronchial lung biopsy.

We report Pneumocystis carinii pneumonia (PCP) diagnosed by bronchoalveolar lavage cytology and transbronchial lung biopsy in three out of five human immunodeficiency virus (HIV) positive adult patients presenting with interstitial pneumonitis. One of these patients was serologically positive for HIV at the time of presentation and the remaining two patients were detected to be HIV positive on follow up after the diagnosis had been established. All the three patients were treated with co-trimoxazole. One patient recovered and was discharged; another patient improved with treatment but died after jugular vein cannulation and the third patient succumbed to cryptosporidial diarrhoea. The remaining two patients with non-specific interstitial pneumonitis treated with prednisolone and bronchodilators were recovered and were discharged from the hospital.

PIP: In developing countries, the proportion of Pneumocystis carinii pneumonia (PCP) cases, compared to other opportunistic infections associated with AIDS, is low partly because of underdiagnosis. PCP cases are reported that were diagnosed by bronchoalveolar lavage (BAL) cytology and transbronchial lung biopsy (TBLB) in 3 out of 5 HIV-positive adult patients presenting with interstitial pneumonitis at the Department of Chest Medicine, KEM Hospital, Bombay. One of these patients was serologically positive for HIV at the time of presentation and the remaining 2 patients were detected to be HIV-positive on follow-up after the diagnosis had been established. All patients had elevated erythrocyte sedimentation rate. CD4+ lymphocyte analysis was done in 1 patient and revealed 360 CD4+ cells/cu. mm. BAL cytology using Giemsa stained smears confirmed the presence of cysts diagnostic of Pneumocystis carinii. TBLBs of the 3 patients who revealed P. carinii in their BAL fluid also evinced foamy intra-alveolar eosinophilic exudates, and the GMS stain showed the presence of ovoid or cup-shaped structures consistent with P. carinii within these exudates. Biopsies from the 2 PCP-negative, HIV-positive patients showed evidence of interstitial pneumonitis. All 3 patients were treated with cotrimoxazole (20 mg/kg body weight). Only 1 patient recovered and was discharged; another patient improved with treatment and was started on cefotaxime (50 mg/kg body weight) and amikacin (15 mg/kg body weight), but died after jugular vein cannulation. The third patient developed cryptosporidial diarrhea and died. The remaining 2 PCP-negative patients with nonspecific interstitial pneumonitis treated with prednisolone and bronchodilators recovered and were discharged from the hospital. BAL cytology and TBLB were useful tools in detecting PCP, one of the few treatable AIDS-related infections.

Anti-inflammatory action of steroid inhalers.

With mucosal inflammation contributing to the pathogenesis of asthma, it is increasingly accepted that long term steroid inhalers may induce remission in chronic long standing asthmatics. The present study involved 44 stable asthmatics who were randomly given either beclomethasone dipropionate inhaler (50 ug) 2 puffs qds or salbutamol inhaler (100 mcg) 2 puffs tds in addition to their oral bronchodilators. Pulmonary function testing, bronchoalveolar lavage and complete blood count were done at basal and weekly intervals and at the end of the study. The absolute eosinophil count showed a significant drop in the beclomethasone group as compared to the salbutamol group. Serial lung functions showed a significant improvement in the pre-bronchodilator PEFR and the pre-bronchodilator FVC in the beclomethasone group as compared to the salbutamol group. There was no significant change in the lavage eosinophil count pre and post-bronchodilator in both groups. Steroid inhalers are thus useful in long term management of bronchial asthma especially with respect to reducing bronchodilator requirement.

Utility of bronchoalveolar lavage in the diagnosis of pulmonary infections in immunosuppressed patients.

AIM: To evaluate the utility of bronchoalveolar lavage (BAL) in immunocompromised patients. MATERIAL AND METHODS: We studied BAL cytology and microbiological culture in 16 kidney transplant recipients (Group A), 14 dialysis patients (Group B) and eight HIV positive patients (Group C) suspected of having pulmonary infections. A group of 21 individuals without pulmonary diseases were studied as controls. RESULTS: A comparison of the cytological profile in controls and study groups showed that percentages of lymphocytes and neutrophils were significantly increased in all three patient groups as compared to controls, BAL bacterial cultures were positive in 4, 3 and 4 cases of Group A, B and C, respectively. Direct examination of BAL cytosmears helped in detecting cytomegalovirus inclusions, acid fast bacilli and Pneumocystis carinii in 3, 2 and 5 cases of Group A, B and C, respectively though microbial cultures were negative. The sensitivity of BAL cytology was found to be 76.3%, whereas that of microbial culture was only 31.5%. The diagnostic yield of BAL was 68.75%, 71.42% and 100% in the Groups A, B and C, respectively, while it was 76% when all three groups were considered together. BAL cytology yielded the diagnosis in 47.36% of cases, a combination of BAL cytology and culture in 23.68% and culture alone in 5.3% of cases. CONCLUSIONS: BAL is useful relatively non-invasive investigative tool in the rapid diagnosis of infections in immunocompromised patients. BAL cytology was found to be more useful than microbial cultures.

Aplidin synergizes with cytosine arabinoside: functional relevance of mitochondria in Aplidin-induced cytotoxicity.

Aplidin (plitidepsin) is a novel marine-derived antitumor agent presently undergoing phase II clinical trials in hematological malignancies and solid tumors. Lack of bone marrow toxicity has encouraged further development of this drug for treatment of leukemia and lymphoma. Multiple signaling pathways have been shown to be involved in Aplidin-induced apoptosis and cell cycle arrest in G1 and G2 phase. However, the exact mechanism(s) of Aplidin action remains to be elucidated. Here we demonstrate that mitochondria-associated or -localized processes are the potential cellular targets of Aplidin. Whole genome gene-expression profiling (GEP) revealed that fatty acid metabolism, sterol biosynthesis and energy metabolism, including the tricarboxylic acid cycle and ATP synthesis are affected by Aplidin treatment. Moreover, mutant MOLT-4, human leukemia cells lacking functional mitochondria, were found to be resistant to Aplidin. Cytosine arabinoside (araC), which also generates oxidative stress but does not affect the ATP pool, showed synergism with Aplidin in our leukemia and lymphoma models in vitro and in vivo. These studies provide new insights into the mechanism of action of Aplidin. The efficacy of the combination of Aplidin and araC is currently being evaluated in clinical phase I/II program for the treatment of patients with relapsed leukemia and high-grade lymphoma.