Cytoskeletal integrity as a drug target

The cytoskeleton provides structural integrity and determines localization of proteins and organelles throughout the cell. The focus on structure and transport has overshadowed the role this ubiquitous network plays in cell signaling cascades, though it participates in transduction of signals from the plasma membrane to the nucleus. Clearly the discovery that neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) brain are made up of the microtubule (MT)-associated protein tau and evidence that the toxic amyloid peptides in AD can lead to tau hyper-phosphorylation and cytoskeletal dystrophy support the assertion that disruption of the MT network is an early signaling event in neurodegenerative cascades. Thus we have been testing the hypothesis that drugs that can moderate such signals through interactions with MTs would protect neurons against Abeta toxicity. Drugs targeted to MTs are currently used as anti-cancer agents, due to their blockade of cell proliferation and induction of cell death. However, we and others have now found that low concentrations of compounds that help stabilize MTs do indeed protect post-mitotic neurons challenged with various toxic stimuli. Therefore we propose that the cytoskeletal network actually serves as a sensor for the overall state of the neurons and a first-line transducer of stress signals. Drugs that can moderate initiation of such early signaling events do protect against disruption of the cytoskeleton and neuritic dystrophy in neuronal cell cultures. In vivo proof-of-concept studies in animal models will require the development of agents that can protect cytoskeletal integrity and also cross the blood brain barrier.     

A locus for hereditary hypotrichosis localized to human chromosome 18q21.1

Hereditary hypotrichosis is a rare autosomal recessive condition characterized clinically by alopecia. Three consanguineous kindreds with multiple affected individuals were ascertained from different regions of Pakistan. A novel hypotrichosis locus was mapped to a 5.5 cM region on chromosome 18q21.1. A maximum two-point LOD score of 5.25 was obtained at marker D18S36 (theta=0.0). Three genes each for desmoglein and desmocollin proteins are located in this region. The expression in epidermal desmosomes and their connection to the keratin intermediate filaments make these genes excellent candidates for recessive hypotrichosis.     

Antiosteoarthritic effect of Punica granatum L. peel extract on collagenase induced osteoarthritis rat by modulation of COL‐2, MMP‐3, and COX‐2 expression

Osteoarthritis (OA) is a chronic degenerative and musculoskeletal disorder. The toxicity associated with nonsteroidal antiinflammatory drugs (NSAIDs) limits its use in the management of OA. To ameliorate these toxicities, natural antioxidants can be used as substitutes for the management of OA. Therefore, this study is aimed to investigate the prophylactic mechanisms of Punica granatum L. peel (PGP) in collagenase‐induced OA rat compared with indomethacin. OA was induced in female Sprague Dawley rats by intraarticular injection of collagenase type‐II and treated with PGP (250 and 500 mg/kg body wt) and a positive control (PC) indomethacin (3 mg/kg body wt). The results demonstrated that PGP reduced the collagenase induced OA as compared with indomethacin treated group through reducing blood ALP (P < .001) and significantly (P < .001) inhibited cartilage erosion as indicated in histological slides with retention of collagen and proteoglycan content. Quantitative real‐time PCR analysis revealed the considerable (P < .05) upregulation in the expression of COL‐2 gene and downregulation of MMP‐3 and COX‐2 genes in the PGP treated group. The high phenolic content (633 ± 1.16 mg/GAE) and flavonoid content (420.3 ± 2.14 mg/RE) contribute to the strong antioxidant activity with IC₅₀ value (320 ± 2.2 μg/mL) of DPPH free radical scavenging activity. These results need further validation in clinical studies and thus, PGP could be developed as a preventive drug treatment for OA.     

Helicobacter pylori: past,current and future treatment strategies with gastroretentive drug delivery systems

Helicobacter pylori have been subject to intense investigation since its discovery from gastric biopsy in 1982. This gastropathogen has been regarded as serious public health problem due to its association with dyspepsia, gastritis, gastroduodenal ulcers, mucus-associated lymphoid tissue lymphoma and gastric carcinoma. In vivo eradication of established H. pylori infections is difficult due to several factors such as gastric niche, coccoid form due to sub-minimum inhibitory concentration of antimicrobials, bacterial load, primary antibiotic resistance, patient compliance and stability of therapeutics in gastric acid secretion. Considering these factors, a logical way to improve the outcome of the treatment is to develop dosage forms which are able to deliver the anti-helicobacter agents in the gastric niche for both local and systemic actions, simultaneously taking care of stability of therapeutics in acidic environment. Such dosage forms, which are popularly known as gastro retentive drug delivery systems (GRDDS), have the immense potential to effectively counter the problem of high bacterial load; prevent induction of coccoid bacteria thereby improving treatment outcome and compliance. This review describes efficacy of various therapeutic agents, treatment strategies and status of different GRDDS until now.     

Similarities between the Forssman carotid syndrome and experimental allergic encephalomyelitis

Summary The Forssman carotid syndrome was induced in guinea pigs to study the mechanism of demyelination-like lesions in this animal model and to compare it with experimental allergic encephalomyelitis (EAE). Acute lesions were studied at 1–3 days after intracarotid injection of rabbit anti-Forssman antibody and chronic lesions at 7–21 days post injection, using routine histological, immunofluorescent, and electron-microscopic techniques. The results were compared to those in a group of guinea pigs with acute or chronic lesions of EAE. The picture was remarkably similar in the two conditions, in regard to localization in the central nervous system (CNS), composition of cellular infiltrates, diameter of lesions produced, myelin loss and axonal degeneration, together with gamma globulin deposition in small vessels in affected areas. The differences were that in the Forssman carotid syndrome, in contrast to EAE, there were no mononuclear cell infiltrates in the acute phase, and no evidence of macrophages invading myelin sheaths was detected. Perivascular lesions consisted of demyelination within infiltrates of mononuclear cell in chronic relapsing EAE, but not in the Forssman carotid syndrome. It is suggested that investigation of the distinction between the two models of the CNS may be of benefit in the pathogenetic study of demyelinating disease.Supported by the Epidemic Myalgic Encephalomyelitis Association and the Multiple Sclerosis Society of Great Britain     

Abdominal Cocoon: Clinical Presentation, Diagnosis, and Management

A 15-year-old girl presented with features suggestive of sub-acute intestinal obstruction (SAIO) with a palpable abdominal lump. Contrast-enhanced computed tomogram (CECT) abdomen revealed congregated small gut loops confined to a single area and encased in a thick membrane suggestive of abdominal cocoon. On laparotomy, a thick white membrane was found encasing most of the small gut. The cocoon was excised releasing the encased small bowel. The patient was relieved of her symptoms following surgery. Histopathology of excised cocoon membrane revealed granulomatous inflammation consistent with tuberculosis. The patient was discharged on ninth postoperative day with advice to take anti-tuberculosis drugs for 6 months. The possibility of abdominal cocoon should be considered in patients with SAIO and abdominal lump. Abdominal cocoon being a rare condition, CECT is useful in clinching the diagnosis and planning elective surgery in experienced hands.     

Spinal Glioblastoma Multiforme: Unusual Cause of Post-Traumatic Tetraparesis

Background/Objective:

Glioblastoma multiforme (GBM) is the most common glial cell tumor of the adult brain. However, primary GBM of the spinal cord is a rare condition.

Methods:

Case report.

Results:

A young man presented with acute onset quadriparesis after a whiplash injury. A magnetic resonance scan showed the typical appearance of a high-grade intramedullary tumor with fusiform expansion of the entire cervical cord. Subtotal decompression and biopsy was done by posterior laminectomy, followed by external beam radiotherapy. Signs and symptoms improved after the completion of radiotherapy but did not resolve completely. Death caused by respiratory failure occurred 3 months later.

Conclusions:

This presentation of GBM of the cervical cord is rare; an intramedullary tumor should be considered when minor cervical trauma results in disproportionate neurologic deficit. To the best of our knowledge, this is the first reported case of spinal GBM with extensive pan-cervical involvement.