Digital Gangrene as a Paraneoplastic Manifestation of Peripheral T-cell Lymphoma Not Otherwise Specified Type.

BACKGROUND: Peripheral T cell lymphoma (PTCL), not otherwise specified (NOS) is a heterogenous group of predominantly nodal T cell lymphomas that generally presents with lymphadenopathy with or without extra nodal involvement. Acral vascular syndrome clinically presents as digital ischemia with Raynaud's phenomenon and acral cyanosis. Although, this condition is commonly associated with connective tissue disorder, smoking and vasculitis, its association with lymphoid malignancy is very rare. Here, we present a case report of a patient with digital gangrene of all toes and fingers as a presenting symptom of PTCL-NOS. CASE DESCRIPTION: A 62 year old male presented with digital ischemia associated with pain, low grade fever, loss of appetite and significant weight loss of 6 kilograms over a period of 3 months. On examination, he was found to have bilateral inguinal and axillary lymph nodes with gangrenous changes over toes and fingers but peripheral pulses were palpable. On evaluation he had anemia, elevated ESR and CRP. CT angiogram revealed thinned out digital arteries with multifocal areas of narrowing. Patient was screened for other causes of digital gangrene and was tested negative for ANCA, ANA, cryoglobulins and viral markers. Lymph node biopsy with IHC was suggestive of peripheral T-cell lymphoma-NOS and was started on CHOP regimen. Lymph nodes size decreased and gangrenous changes resolved. CONCLUSION: Though digital ischemia is a rare paraneoplastic presentation of lymphoma, it should be considered if there is a rapid progression of gangrene. Early initiation of chemotherapy may result in the reduction of further progression of digital gangrene and thus prevent permanent disability. In our patient, progression of gangrene was prevented even though it was an aggressive variant of T cell lymphoma.

Pinch Purpura in Adult Colloid Milium-A Case Report.

Colloid milium is a rare cutaneous deposition disorder characterized by the presence of asymptomatic multiple dome-shaped semi-translucent waxy yellowish or skin-colored papules. It is commonly seen on the face and dorsum of forearms and arms due to chronic sun exposure. Nodular amyloidosis and primary systemic amyloidosis mimic adult colloid milium more closely. They share indistinguishable common features clinically and histologically. Purpura following trivial injury is a cardinal feature of primary systemic amyloidosis. Here, we are reporting a case of adult colloid milium, presented with waxy papules and purpura involving the dorsa of the lower half of the forearms and hands which is confirmed by histopathological and immunohistochemical studies.

A meta-learning framework using representation learning to predict drug-drug interaction.

MOTIVATION: Predicting Drug-Drug Interaction (DDI) has become a crucial step in the drug discovery and development process, owing to the rise in the number of drugs co-administered with other drugs. Consequently, the usage of computational methods for DDI prediction can greatly help in reducing the costs of in vitro experiments done during the drug development process. With lots of emergent data sources that describe the properties and relationships between drugs and drug-related entities (gene, protein, disease, and side effects), an integrated approach that uses multiple data sources would be most effective. METHOD: We propose a semi-supervised learning framework which utilizes representation learning, positive-unlabeled (PU) learning and meta-learning efficiently to predict the drug interactions. Information from multiple data sources is used to create feature networks, which is used to learn the meta-knowledge about the DDIs. Given that DDIs have only positive labeled data, a PU learning-based classifier is used to generate meta-knowledge from feature networks. Finally, a meta-classifier that combines the predicted probability of interaction from the meta-knowledge learnt is designed. RESULTS: Node2vec, a network representation learning method and bagging SVM, a PU learning algorithm, are used in this work. Both representation learning and PU learning algorithms improve the performance of the system by 22% and 12.7% respectively. The meta-classifier performs better and predicts more reliable DDIs than the base classifiers.

Role of sesamol-loaded floating beads in gastric cancers: a pharmacokinetic and biochemical evidence.

CONTEXT: Sesamol, a potential antioxidant with marked anticancer potential suffers from issues of extensive tissue distribution and local gastric irritation on oral administration. OBJECTIVE: To develop multiunit gastro-retentive floating beads (S-FBs) for localised and prolonged release of sesamol to treat gastric cancers. MATERIALS AND METHODS: S-FBs prepared using calcium carbonate, sodium alginate and hydroxypropylmethyl cellulose (HPMC) in different proportions, were characterised and evaluated in vivo in N-methyl-N-nitro-N-nitroguanidine-induced gastric cancer in rats. Single oral dose plasma pharmacokinetic study was also performed for free sesamol and S-FBs. RESULTS AND DISCUSSION: Restraining sesamol in floating beads, significantly lowered the release (diffusion controlled) rate, increased t50% (31 times) and reduced its in vivo clearance (>1.5 times). Preclinical evaluation showed S-FBs (10 mg/kg) to be significantly better than free sesamol and better/equivalent to methotrexate (2 mg/kg). CONCLUSION: Most of the natural phytochemical or antioxidants show pretreatment effectiveness. We, however, developed and established S-FBs for sustained curative effect.

Sesamol-loaded solid lipid nanoparticles for treatment of skin cancer.

Abstract Role of reactive oxygen species (ROS) in skin carcinogenesis is well documented. Natural molecules, like sesamol, with marked antioxidant potential can be useful in combating skin cancers. In vitro antiproliferative (using MTT assay) and DNA fragmentation studies in HL 60 cell lines, confirmed the apoptotic nature of sesamol. However, it showed a significant flux across the mice skin upon topical application, such that its local availability in skin is limited. Former is attributed mainly to its properties like small size, low molecular weight (138.28), and a sufficient lipid and water solubility (log P 1.29; solubility 38.8 mg/ml). To achieve its maximum epicutaneous delivery, packaging it into a suitable carrier system is thus indicated. Sesamol-loaded solid lipid nanoparticles (S-SLN) were thus prepared with particle size of 127.9 nm (PI: 0.256) and entrapment efficiency of 88.21%. Topical application of S-SLN in a cream base indicated significant retention in the skin with minimal flux across skin as confirmed by the in-vivo skin retention and ex-vivo skin permeation studies. In vivo anticancer studies performed on TPA-induced and benzo(a)pyrene initiated tumour production (ROS mediated) in mouse epidermis showed the normalization (in histology studies) of skin cancers post their induction, upon treatment with S-SLN.

The role of ubiquitin in neurotrophin receptor signalling and sorting.

NGF (nerve growth factor) binding to TrkA (tropomyosin receptor kinase A) induces dimerization, autophosphorylation and internalization of the receptor to signalling vesicles for delivery of differentiation signals. TrkA interacts with p75 receptor through the p62-TRAF-6 (tumour-necrosis-factor-receptor-associated factor 6) complex bridging the two receptors. The atypical protein kinase C is activated and recruited to the receptor complex as well. TrkA is Lys63-polyubiquitinated on Lys485 by the E3 (ubiquitin ligase), TRAF-6, and E2 (ubiquitin-conjugating enzyme), UbcH7. Inhibition of polyubiquitination has been observed to interrupt signalling and internalization. Furthermore, an absence of p62 prevents endosomal localization and signalling. Altogether, these findings reveal Lys63-linked polyubiquitin chains and the shuttling protein p62 co-ordinately regulate TrkA internalization, trafficking and sorting.

Nerve growth factor stimulates multisite tyrosine phosphorylation and activation of the atypical protein kinase C's via a src kinase pathway.

Atypical protein kinase C (PKC) isoforms are required for nerve growth factor (NGF)-initiated differentiation of PC12 cells. In the present study, we report that PKC-iota becomes tyrosine phosphorylated in the membrane coincident with activation posttreatment with nerve growth factor. Tyrosine phosphorylation and activation of PKC-iota were inhibited in a dose-dependent manner by both PP2 and K252a, src and TrkA kinase inhibitors. Purified src was observed to phosphorylate and activate PKC-iota in vitro. In PC12 cells deficient in src kinase activity, both NGF-induced tyrosine phosphorylation and activation of PKC-iota were also diminished. Furthermore, we demonstrate activation of src by NGF along with formation of a signal complex including the TrkA receptor, src, and PKC-iota. Recruitment of PKC-iota into the complex was dependent on the tyrosine phosphorylation state of PKC-iota. The association of src and PKC-iota was constitutive but was enhanced by NGF treatment, with the src homology 3 domain interacting with a PXXP sequence within the regulatory domain of PKC-iota (amino acids 98 to 114). Altogether, these findings support a role for src in regulation of PKC-iota. Tyrosine 256, 271, and 325 were identified as major sites phosphorylated by src in the catalytic domain. Y256F and Y271F mutations did not alter src-induced activation of PKC-iota, whereas the Y325F mutation significantly reduced src-induced activation of PKC-iota. The functional relevance of these mutations was tested by determining the ability of each mutant to support TRAF6 activation of NF-kappaB, with significant impairment by the Y325F PKC-iota mutant. Moreover, when the Y352F mutant was expressed in PC12 cells, NGF's ability to promote survival in serum-free media was reduced. In summary, we have identified a novel mechanism for NGF-induced activation of atypical PKC involving tyrosine phosphorylation by c-Src.

Anti-inflammatory activity of lupeol and lupeol linoleate in rats.

Two pentacyclic triterpenes, namely lupeol and lupeol linoleate, were investigated for their anti-inflammatory, antinociceptive, anti-pyretic and ulcerogenic properties in comparison with the commonly used non-steroidal anti-inflammatory drug, indomethacin in rats. Lupeol, lupeol linoleate and indomethacin showed a reduction in paw swelling by 39, 58 and 35%, respectively, in adjuvant arthritis. Triterpenes were devoid of any antinociceptive, anti-pyretic and ulcerogenic actions. However, indomethacin exhibited a positive response to these properties. These results suggest that the mechanism of action of triterpenes is different from the non-steroidal anti-inflammatory drug.

Applications of immobilized stationary-phase liquid chromatography: a potential in vitro technique.

Immobilized artificial-membrane chromatography is a potential in vitro technique for determining lipophilicity and studying drug transport and membrane interactions. It is reproducible, efficient and simple. Several other and newer applications of immobilized stationary-phase liquid chromatography have been reported, including the purification of membrane proteins, the synthesis of biomolecules and the simultaneous determination of enzyme activity and enantioselectivity. This article describes the immobilized artificial-membrane concept and provides an overview of the applications, advantages and limitations, in general, of immobilized stationary-phase chromatography.

Anticomplement activity of triterpenes from Crataeva nurvala stem bark in adjuvant arthritis in rats.

Adjuvant arthritis is widely used as an experimental model for rheumatoid arthritis and inflammation. It is useful in the evaluation of anti-inflammatory drugs. Lupeol is a naturally occuring triterpene isolated from Crataeva nurvala stem bark, and its ester lupeol linoleate was synthesized. The effects of lupeol and lupeol linoleate on the development of complement in adjuvant arthritis in rats were studied and compared with those of indomethacin. The effect of lupeol linoleate in reducing the foot-pad thickness and complement activity in arthritic rats was even greater than that of unesterified lupeol and indomethacin. Because complement is highly involved in inflammation, the results suggest that the anti-inflammatory activity of triterpenes may be due to their anticomplementary activity.

Effect of lupeol and lupeol linoleate on lysosomal enzymes and collagen in adjuvant-induced arthritis in rats.

Lysosomal enzymes play important roles in the inflammatory process. The pentacyclic triterpenes, lupeol and lupeol linoleate were administered orally (50 mg/kg) for 8 days to arthritic rats, after 11th day of adjuvant injection. The lysosomal enzymes were significantly increased in arthritic condition, which are involved in the destruction of structural macromolecules in connective tissue and cartilage in rheumatoid arthritis. Hence the level of collagen was significantly decreased and the excretion of urinary hydroxyproline, hexosamine, hexuronic acid and glycosaminoglycans were increased in arthritic rats. Treatment of arthritic rats with triterpenes reversed the above changes, which may be due to stabilization of the lysosomal membrane. Out of the two triterpenes tested, lupeol linoleate showed better ameliorating action than lupeol.

Effect of Vernonia cinerea Less flower extract in adjuvant-induced arthritis.

1. The anti-inflammatory effect of an alcoholic extract from the flower of Vernonia cinerea (Asteraceae; Less) was tested in adjuvant arthritic rats. 2. Changes in paw volume, body and tissue weights and serum and tissue enzyme activities of ALT, AST, ACP and cathepsin-D in adjuvant rats were reversed by oral administration of 100 mg/kg body weight (BW) of the flower extract. 3. The extract also reversed the major histopathological changes in the hindpaws of the arthritic rats. 4. Phytochemical studies revealed the presence of alkaloids, saponins, steroids and flavonoids. 5. It is concluded that the extract contains as yet unidentified anti-inflammatory principle(s).

Effect of triterpenes from Crataeva nurvala stem bark on lipid peroxidation in adjuvant induced arthritis in rats.

Lupeol, a pentacyclic triterpene was isolated from C. nurvala stem bark and its ester lupeol linoleate was synthesised. These triterpenes were tested for their anti-inflammatory activity in complete Freund's adjuvant induced arthritis rats. For some time free radicals have been implicated in damage to connective tissues during inflammatory conditions and arthritis. Lupeol and lupeol linoleate were administered orally at the dose level of 50 mg kg-1 body weight daily for 8 days, from the 11th to 18th day postadjuvantly. There was a significant increase in lipid peroxide level in plasma of arthritic rats but it was found to be decreased in the liver. The antioxidant enzymes superoxide dismutase, glutathione peroxidase and catalase were elevated in both the liver and haemolysate in adjuvant-induced rats. Blood glutathione was decreased in arthritis. The triterpenes reduced the above alterations produced in arthritic animals. The effect of lupeol linoleate was found to be better in this respect when compared with lupeol.

A multicentre study of perinatal mortality in Nepal.

A prospective survey was carried out in two Kathmandu hospitals and two rural districts to establish urban and rural perinatal mortality rates (PNMRs) for these four centres in Nepal and to ascertain the causes of perinatal mortality. All perinatal deaths occurring over a 1-year period in the four centres were included (during which time there was a total of 14,967 births). Cause of death was established by contemporary review of hospital case records or by structured questionnaire ('verbal autopsy') in the rural areas. The PNMRs in the hospitals were 48.0 and 23.7 per thousand total births respectively, whilst those of the rural settings were 96.2 and 42.5 per thousand births. Perinatal asphyxia, low birthweight and infection were the most common causes but many of the deaths were unexplained. The high mortality rates were felt to reflect the difficult circumstances of childbirth in Nepal. It was concluded that a number of interventions would appear appropriate, but that these should be introduced in a scientific manner.

PIP: A prospective survey was carried out in 2 Kathmandu hospitals and 2 rural districts to establish urban and rural perinatal mortality rates (PNMRs) and to ascertain the causes of perinatal mortality. The sites chosen for community-based studies were in Lalitpur district in the Kathmandu valley and Jumla in the remote north-west of Nepal as the second site. All perinatal deaths occurring over a 1-year period in the 4 centers were included. Cause of death was established by contemporary review of hospital case records or by structured questionnaire in the rural areas. The previous pregnancy was a live birth in 82% of cases at the Maternity Hospital, in 76% at Patan Hospital, in 87% in Jumla, and in 79% of cases from Lalitpur. On the other hand the overall poor outcome from previous pregnancies appeared to correlate with the present perinatal mortality rates. The PNMRs in the hospitals were 48.0 and 23.7 per 1000 total births, respectively, while those of the rural settings were 96.2/1000 and 42.5/1000 births. Perinatal asphyxia, low birth weight, and infection were the most common causes, but many of the deaths were unexplained. 32% of women at the Maternity Hospital had a previous pregnancy loss compared with 29% at Patan Hospital, 24% at Lalitpur and at Jumla. At Patan Hospital nearly 90% of patients had attended an antenatal clinic. Conversely, at the Maternity Hospital only 40% of women with a perinatal loss had received antenatal care; and in Jumla and Lalitpur less than 20% of women had. In Jumla 79% of the perinatal deaths were preterm and in Lalitpur 50%. At Patan Hospital, the PNMR in this weight category was 769.2/1000 and at Maternity Hospital 876.6/1000 total births. PNMRs were higher for male infants in the Maternity Hospital (51.7/1000 vs. 43/1000), in Patan Hospital (32/1000 vs. 15/1000), and in Jumla (108/1000 vs. 81/1000). Recognized risk factors for perinatal mortality were confirmed, such as increasing parity, increasing age, and being male.