Impact of visual impairment on use of caregiving by individuals with age-related macular degeneration

BACKGROUND: To assess the patient-reported use of caregiving among individuals with age-related macular degeneration (AMD) and evaluate the impact of visual impairment level on this use. METHODS: A survey including the AMD Health and Impact Questionnaire and the Daily Living Tasks Dependent on Vision Questionnaire (DLTV) was mailed to members of the Macular Degeneration Partnership. The study was approved by an institutional review board, and respondents provided consent before participating. Responses were analyzed by estimated visual acuity determined by scores from the DLTV. Deidentified data were analyzed using SAS Version 8.2 (SAS Institute, Cary, NC). RESULTS: Of 803 respondents, 56% were male, and the mean age was 73 years. Use of paid and unpaid help significantly increased as visual acuity decreased. Using a national average for caregiver time, annual costs for caregiving ranged from 225 to 47,086 US dollar depending on visual acuity. CONCLUSION: There are substantial differences in caregiver support with increased AMD severity. Delaying progression of AMD could result in considerable cost savings.     

Betulinic acid derivatives as anticancer agents: structure activity relationship

Betulinic acid, a pentacyclic triterpene, is widely distributed throughout the tropics. It possesses several biological properties such as anticancer, anti-inflammatory, antiviral, antiseptic, antimalarial, spermicidal, antimicrobial, antileshmanial, antihelmentic and antifeedent activities. However, betulinic acid was highly regarded for its anticancer and anti-HIV activities. Anticancer role of betulinic acid appeared by inducing apoptosis in cells irrespective of their p53 status. Due to high order safety in betulinic acid, a number of structural modifications carried out to improve its potency and efficacy. The C-1, C-2, C-3, C-4, C-20 and C-28 positions are the diversity centers in betulinic acid, and the derivatives resulted on various structural modifications at these positions screened for their anticancer activity. This review presents the structure activity relationship carried out on C-1, C-2, C-3, C-4, C-20, C-28, A-ring, D-ring and E-ring modified betulinic acid derivatives. We have compiled the most active betulinic acid derivatives along with their activity profile in each series. Structure activity relationship studies revealed that C-28 carboxylic acid was essential for the cytotoxicity. The halo substituent at C-2 position in betulinic acid enhanced the cytotoxicity. Though the relation of the cytotoxicity with the nature of substituents at C-3 position could not be generalized but the ester functionality appeared to be a better substituent for enhancing the cytotoxicity. An interesting observation is that the three rings skeleton (A, B and C rings) had played an important role in eliciting anticancer activity, which could be a new molecular skeleton to design new anticancer drugs.     

Regression of melanoma in a murine model by RLIP76 depletion

RLIP76/RALBP1 is a stress-responsive membrane protein implicated in the regulation of multiple cellular signaling pathways. It represents the predominant glutathione-conjugate transporter in cells, and our previous studies have shown that its inhibition by antibodies or depletion by short interfering RNA (siRNA) causes apoptosis in a number of cancer cell types. The present studies were done to explore the potential clinical applicability of our previous observations by comparing the relative expression of RLIP76 in cancer versus normal cell lines and to determine whether depletion of RLIP76 activity can exert cancer-specific apoptosis. RLIP76 expression was found to be significantly greater in malignant cells compared to nonmalignant cells. Inhibition of RLIP76, using antibodies towards a cell surface epitope, or depletion of RLIP76 using either siRNA or antisense phosphorothioate oligonucleotides preferentially caused apoptosis in malignant cells. More importantly, in vivo studies showed that administration of RLIP76 antibodies, siRNA, or antisense oligonucleotides to mice bearing syngeneic B16 mouse melanoma cells caused complete tumor regression within 10 days. These findings strongly suggest that RLIP76 depletion by genetic approaches or inhibition by antibodies may be a clinically viable antineoplastic therapy, particularly for melanoma.     

Cyclin D1 induction of cellular migration requires p27(KIP1)

The cyclin D1 gene is amplified and overexpressed in human breast cancer, functioning as a collaborative oncogene. As the regulatory subunit of a holoenzyme phosphorylating Rb, cyclin D1 promotes cell cycle progression and a noncatalytic function has been described to sequester the cyclin-dependent kinase inhibitor protein p27. Cyclin D1 overexpression correlates with tumor metastasis and cyclin D1-deficient fibroblasts are defective in migration. The genetic mechanism by which cyclin D1 promotes migration and movement is poorly understood. Herein, cyclin D1 promoted cellular migration and cytokinesis of mammary epithelial cells. Cyclin D1 enhanced cellular migratory velocity. The induction of migration by cyclin D1 was abolished by mutation of K112 or deletion of NH(2)-terminal residues 46 to 90. These mutations of cyclin D1 abrogated physical interaction with p27(KIP1). Cyclin D1(-/-) cells were p27(KIP1) deficient and the defect in migration was rescued by p27(KIP1) reintroduction. Conversely, the cyclin D1 rescue of cyclin D1(-/-) cellular migration was reversed by p27(KIP1) small interfering RNA. Cyclin D1 regulated p27(KIP1) abundance at the posttranslational level, inhibiting the Skp2 promoter, Skp2 abundance, and induced p27(KIP1) phosphorylation at Ser(10). Together, these studies show cyclin D1 promotes mammary epithelial cell migration. p27(KIP1) is required for cyclin D1-mediated cellular migration.     

p27Kip1 repression of ErbB2-induced mammary tumor growth in transgenic mice involves Skp2 and Wnt/beta-catenin signaling

Expression of the cyclin-dependent kinase (Cdk) inhibitor (p27(Kip1)) is frequently reduced in human tumors, often correlating with poor prognosis. p27(Kip1) functions as a haploinsufficient tumor suppressor; however, the mechanism by which one allele of p27(Kip1) regulates oncogenic signaling in vivo is not well understood. We therefore investigated the mechanisms by which p27(Kip1) inhibits mammary tumor onset. Using the common background strain of FVB, p27(Kip1) heterozygosity (p27(+/-)) accelerated ErbB2-induced mammary tumorigenesis. We conducted microarray analyses of mammary tumors developing in mice with genetic haploinsufficiency for p27(Kip1) expressing a mammary-targeted ErbB2 oncogene. Global gene expression profiling and Western blot analysis of ErbB2/p27(+/-) tumors showed that the loss of p27(Kip1) induced genes promoting lymphangiogenesis, cellular proliferation, and collaborative oncogenic signaling (Wnt/beta-catenin/Tcf, Cdc25a, Smad7, and Skp2). Skp2 expression was induced by ErbB2 and repressed by p27(Kip1). Degradation of p27(Kip1) involves an SCF-type E3 ubiquitin ligase, including Skp2. The Skp2 component of the SCF(SKP2) complex that degrades p27(Kip1) was increased in ErbB2 tumors correlating with earlier tumor onset. In both murine and human ErbB2-overexpressing breast cancers, p27(Kip1) levels correlated inversely with Skp2. p27(Kip1) haploinsufficiency activated Wnt/beta-catenin/hedgehog signaling. Reintroduction of p27(Kip1) inhibited beta-catenin induction of Tcf-responsive genes (Siamosis, c-Myc, and Smad7). p27(Kip1) is haploinsufficient for ErbB2 mammary tumor suppression in vivo and functions to repress collaborative oncogenic signals including Skp2 and Wnt/beta-catenin signaling.     

Squamous cell carcinoma of the maxillary sinus: a Tata Memorial Hospital experience

BACKGROUND: The optimal treatment of maxillary sinus carcinoma remains to be defined and there is a paucity of Indian studies on the subject. AIMS: To present experience of management of squamous cell carcinoma of the maxillary sinus treated with curative intent at a single institution. SETTINGS AND DESIGN: Retrospective study of patients with squamous cell carcinoma of the maxillary sinus who presented between 1994 to 1999. MATERIALS AND METHODS: The records of 73 patients with squamous cell carcinoma of the maxillary sinus were analyzed. Sixty-two patients were evaluable. Forty patients (65%) were treated with surgery followed by postoperative radiotherapy, five patients (8%) were treated with radiotherapy alone, five patients (8%) were treated with surgery alone; 12 patients (19%) received chemotherapy. Statistical analysis used: Statistical analysis was done using Kaplan-Meier method. RESULTS: The majority of patients presented with locally advanced disease (52, 84%); nodal involvement was observed in five patients (8%). The most common site of recurrence was at the primary site, which was observed in 28 patients (45%) and regional failures occurred in 10 (16%). The 3 and 5-year overall survival was 38% and 35% and the disease free survival was 29% and 26% respectively. The 5-year overall survival after surgery and postoperative radiotherapy was 42%. CONCLUSIONS: The majority of patients present with advanced disease resulting in poor outcomes to conventional treatment modalities. Locoregional tumor progression remains a significant pattern of failure. New approaches such as neoadjuvant or concomitant chemoradiotherapy with aggressive surgery need to be considered and evaluated in prospective studies.     

Spontaneous transmural migration of surgical sponges

Postoperative retained surgical sponges or other foreign bodies are usually underreported. Radio-opaque materials are usually detected on follow-up radiological investigations, but radiolucent materials such as sponges create diagnostic problems and clinically mimic various abdominal pathologies. Introduction of spiral computed tomography, magnetic resonance imaging and dedicated ultrasonography has enabled clinicians to find these foreign bodies at the earliest opportunity to avoid disastrous complications. Spontaneous transmural migration and expulsion per rectum of more than one sponge without sequelae is also possible. We report one such interesting case.     

Intimo-intimal intussusception of the aorta

A 50-year-old man presented with acute onset of chest pain. Subsequent transesophageal echocardiography and computed tomography scan showed absence of a flap in the ascending aorta and a clear dissection flap involving the arch and descending aorta. Magnetic resonance imaging showed a tear and a small flap in the right coronary sinus. During surgery, we found a total circumferential intimal tear at the sinotubular junction with intimo-intimal intussusception of the internal channel into the arch. Dissection without intimal flap and aortic intussusception is a rare form of type A dissection, which is difficult to diagnose on routine investigations and can delay treatment.