The newer unconventional indications of permanent pacemakers

In recent years, the indications for permanent pacemakers have expanded. The interest has focussed on hypertrophic cardiomyopathy, dilated cardiomyopathy and a new entity called hypertensive hypertrophy with cavity obliteration (HHCO). Pacemaker therapy is establishing itself for the prevention of atrial fibrillation. Pacing for neurocardiogenic syncope with newer pacing mode has encouraging datas. Pacemaker for long QT syndrome, after cardiac transplant and for haemodynamic improvement in occasional cases of first degree atrio-ventricular block is getting attention. The AHA and ACC guidelines updated in 1998 for implantation of cardiac pacemakers, now include several of these newer indications.     

Modeling adverse environmental impacts on the reproductive system

When priority topics are being established for the study of women's health, it is generally agreed that one important area on which to focus research is reproduction. For example, increasing attention has been directed to environmental exposures that disrupt the endocrine system and alter reproduction. These concerns also suggest the need to give greater attention to the use of animal toxicologic testing to draw inferences about human reproductive risks. Successful reproduction requires multiple simultaneous and sequential processes in both the male and female, and the effect of toxicity on reproduction-related processes is time dependent. Currently, however, the risk assessment approach does not allow for the use of multiple processes or for considering the reproductive process response as a function of time. We discuss several issues in modeling exposure effects on reproductive function for risk assessment and present an overview of approaches for reproductive risk assessment. Recommendations are provided for an effective animal study design for determining reproductive risk that addresses optimization of the duration of dosing, observation of the effects of exposure on validated biomarkers, analysis of several biomarkers for complete characterization of the exposure on the underlying biologic processes, the need for longitudinally observed exposure effects, and a procedure for estimating human reproductive risk from the animal findings. An approach to characterizing reproductive toxicity to estimate the increased fertility risks in a dibromochloropropane (DBCP)-exposed human population is illustrated, using several reproductive biomarkers simultaneously from a longitudinal rabbit inhalation study of DBCP and an interspecies extrapolation method.     

Phase II trial of bortezomib for patients with advanced renal cell carcinoma.

PURPOSE: To assess the efficacy and toxicity of bortezomib (Velcade; Milennium Pharmaceuticals Inc, Cambridge, MA; formerly PS-341) in patients with metastatic renal cell carcinoma (RCC). PATIENTS AND METHODS: Thirty-seven patients with metastatic RCC were treated with bortezomib. The first 25 patients enrolled onto the trial were treated with a dose of 1.5 mg/m2. The dose was decreased to 1.3 mg/m2 for the subsequent 12 patients, because more than 50% of the patients treated at the higher dose required dose reductions. Bortezomib was given by intravenous administration on a twice-weekly schedule for 2 weeks followed by 1 week without treatment until progression or unacceptable toxicity occurred. Twenty-three patients (62%) previously had undergone nephrectomy, and 19 patients (51%) had previously been treated with cytokine therapy. RESULTS: Of the 37 assessable patients, the best response was a partial response in four patients (11%; 95% CI, 3% to 25%) and stable disease in 14 patients (38%; 95% CI, 23% to 55%). The four patients with partial response experienced response durations of 8, 8+, 15+, and 20+ months. Grade 2 or 3 sensory neuropathy was present in 10 patients (53%) overall. One patient in the 1.5 mg/m2 group had grade 3 sensory neuropathy; no grade 3 sensory neuropathy was seen in the 1.3 mg/m2 group. CONCLUSION: The results of this trial suggest that bortezomib has an antitumor effect in individual patients with metastatic RCC. The small proportion of patients who achieved a partial response does not support routine use in metastatic RCC. Efforts to identify the molecular profile associated with clinical response or combination therapy with interferon alfa or other novel agents, may be considered.     

Analysis of COVID-19-associated rhino-orbital-cerebral mucormycosis patients in a tertiary care center in Northern India

Purpose:An unprecedented surge has been noted in rhino-orbital-Cerebral mucormycosis (ROCM) in times of current COVID-19 pandemic. The present prospective study aims to evaluate clinico-epidemiological profile, risk factors, management, and outcome of the cases of ROCM that presented to our tertiary care center during the study period from April to June 2021.Methods:All patients were subjected to complete history taking, ophthalmological examination, and imaging studies. The patients were staged and were treated with intravenous liposomal amphotericin B (AMB) and sino-nasal debridement of local necrotic tissue. Transcutaneous retrobulbar AMB (TRAMB), orbital decompression, and exenteration were instituted as indicated. All patients were followed up for a minimum of 6 months before arriving at the final outcome. Statistical analysis was performed.Results:A total of 49 patients presented during the study period, with a mean age of 42.2 years. The major risk factors included uncontrolled diabetes (89.8%), COVID-19 positivity (51.02%), and concurrent steroid use (38.77%). The most common presenting symptom was facial pain/swelling (43.65%), while the most common presenting sign was deterioration in vision (75.51%). Intravenous liposomal AMB was given to all patients along with sino-nasal debridement (85.71%), TRAMB (57.14%), orbital decompression (14.28%), and exenteration (12.24%). Overall, mortality at 6 months was 22.45% (11 patients). Age more than 60 years, intracranial extension, and HbA1c of more than 8.0% were observed to be statistically significant indicators of mortality.Conclusion:Early suspicion and timely diagnosis of mucormycosis at rhino-orbital stage is warranted in order to salvage life as well as visual function. TRAMB may prove as potentially favorable treatment modality in cases with limited orbital involvement.     

Exploration and insights into the cellular internalization and intracellular fate of amphiphilic polymeric nanocarriers

The beneficial or deleterious effects of nanomedicines emerge from their complex interactions with intracellular pathways and their subcellular fate. Moreover, the dynamic nature of plasma membrane accounts for the movement of these nanocarriers within the cell towards different organelles thereby not only influencing their pharmacokinetic and pharmacodynamic properties but also bioavailability, therapeutic efficacy and toxicity. Therefore, an in-depth understanding of underlying parameters controlling nanocarrier endocytosis and intracellular fate is essential. In order to direct nanoparticles towards specific sub-cellular organelles the physicochemical attributes of nanocarriers can be manipulated. These include particle size, shape and surface charge/chemistry. Restricting the particle size of nanocarriers below 200 nm contributes to internalization via clathrin and caveolae mediated pathways. Similarly, a moderate negative surface potential confers endolysosomal escape and targeting towards mitochondria, endoplasmic reticulum (ER) and Golgi. This review aims to provide an insight into these physicochemical attributes of nanocarriers fabricated using amphiphilic graft copolymers affecting cellular internalization. Fundamental principles understood from experimental studies have been extrapolated to draw a general conclusion for the designing of optimized nanoparticulate drug delivery systems and enhanced intracellular uptake via specific endocytic pathway.KEY WORDS: Amphiphilic, Copolymer, Nanoparticles, Internalization, Intracellular fate     

Validation of Adult Relative Radiation Levels Using the ACR Dose Index Registry: Report of the ACR Appropriateness Criteria Radiation Exposure Subcommittee

The ACR Dose Index Registry (DIR) provides a new source of clinical radiation exposure data that has not been used previously to establish or update the relative radiation level (RRL) values in the ACR Appropriateness Criteria (AC). The results of a recent review of DIR data for 10 common CT examinations were compared with current ACR AC RRL values for the same procedures. The AC RRL values were previously determined by consensus of members of the AC Radiation Exposure Subcommittee based on reference radiation dose values from the literature (when available) and anecdotal information from individual members’ clinical practices and experiences. For 7 of the 10 examination types reviewed, DIR data agreed with existing RRL values. For 3 of 10 examination types, DIR data reflected lower dose values than currently rated in the AC. The Radiation Exposure Subcommittee will revise these RRL assignments in a forthcoming update to the AC (in October 2018) and will continue to monitor the DIR and associated reviews and analyses to refine RRL assignments for additional examination types. Given recent attention and efforts to reduce radiation exposure in CT and other imaging modalities, it is likely that other examination types will require revision of RRL assignments once information from the DIR database is considered.     

Expression of p27 in Residual Rectal Cancer after Preoperative Chemoradiation Predicts Long-term Outcome

Background: Compared with surgery alone, preoperative radiotherapy and 5-fluorouracil–based chemotherapy (combined-modality therapy; CMT) improves outcomes in patients with locally advanced rectal cancer. Although numerous studies have focused on identifying molecular markers of prognosis in the primary rectal cancer before CMT, our aim was to identify markers of prognosis in residual rectal cancer after preoperative CMT.Methods: Sixty-seven patients with locally advanced (T3–4 and/or N1) rectal cancer were treated with preoperative radiotherapy (median, 5040 cGy) with or without 5-fluorouracil–based chemotherapy. Residual tumor in the resected specimen, available for 52 patients, was analyzed for tumor-node-metastasis stage, lymphovascular and/or perineural invasion, and immunohistochemical expression of p27, p21, p53, Ki-67, retinoblastoma gene, cyclin D1, and bcl-2. Recurrence-free survival (RFS) was determined by the Kaplan-Meier method and compared by the log-rank test.Results: With a median follow-up of 69 months, the overall 5-year RFS was 74%. RFS was significantly worse for patients with positive p27 expression (P = .005), T3–4 tumors (P = .02), and positive lymph nodes (P = .04) in the irradiated specimen. On multivariate analysis, positive p27 expression remained an independent negative prognostic factor for RFS (P = .04). None of the other proteins was significantly associated with RFS.Conclusions: Our results indicate that positive p27 expression in rectal cancer after preoperative chemoradiation is an independent negative predictor of RFS. Expression of p27 in the residual rectal cancer may therefore identify patients with disease likely to be refractory to standard therapy and for whom investigational approaches should be strongly considered.the 56th Annual Cancer Symposium, Society of Surgical Oncology, Los Angeles, California, March 5–9, 2003.     

Protein Folding Activity of the Ribosome (PFAR) –– A Target for Antiprion Compounds

Prion diseases are fatal neurodegenerative diseases affecting mammals. Prions are misfolded amyloid aggregates of the prion protein (PrP), which form when the alpha helical, soluble form of PrP converts to an aggregation-prone, beta sheet form. Thus, prions originate as protein folding problems. The discovery of yeast prion(s) and the development of a red-/white-colony based assay facilitated safe and high-throughput screening of antiprion compounds. With this assay three antiprion compounds; 6-aminophenanthridine (6AP), guanabenz acetate (GA), and imiquimod (IQ) have been identified. Biochemical and genetic studies reveal that these compounds target ribosomal RNA (rRNA) and inhibit specifically the protein folding activity of the ribosome (PFAR). The domain V of the 23S/25S/28S rRNA of the large ribosomal subunit constitutes the active site for PFAR. 6AP and GA inhibit PFAR by competition with the protein substrates for the common binding sites on the domain V rRNA. PFAR inhibition by these antiprion compounds opens up new possibilities for understanding prion formation, propagation and the role of the ribosome therein. In this review, we summarize and analyze the correlation between PFAR and prion processes using the antiprion compounds as tools.     

Immunocytochemical Localization of Vasoactive Intestinal Peptide and Substance P in the Colon from Normal Subjects and Patients with Inflammatory Bowel Disease

Neuropeptides form a part of the brain-gut axis which may regulate gastrointestinal functions, including immune regulation. Various changes in the neuropeptides--most important, vasoactive intestinal peptide and substances P (VIP and SP)--have been described in inflammatory bowel disease. We employed a sensitive immunoperoxidase (avidin-biotin-peroxidase complex) technique, using anti-VIP and anti-SP antibodies to localize and compare the distribution of VIP and SP in the colon. Colon specimens from 19 normal subjects, eight patients with ulcerative colitis (UC), and eight with Crohn's disease (CD) were used. In the normal colon, VIP and SP immunoreactivity (IR) were localized in the muscularis mucosa, circular muscles, walls of blood vessels, nerve fibers, and some distinct cells, probably enterochromaffin cells. SP-IR was also present in the epithelial cells, mainly along the basolateral domain. VIP-IR was considerably diminished at all locations in patients with UC and CD. However, the SP-IR was increased in UC in the colonic epithelial cells along the basolateral areas. The SP-IR was intense in patients with CD, in the epithelium, the granulomas, cells lining the mucosal fissure, and in the muscle layers. In contrast to normals, SP-IR in patients with CD was observed both in the longitudinal and circular muscles. We conclude that VIP-IR and SP-IR are distributed widely in the mucosa, submucosa, and in the circular muscle in normal colon. VIP-IR is decreased in UC and CD, whereas SP-IR is increased in both, but more so in CD.     

Study into the iron content of seminal plasma in normal and infertile subjects

The iron content in seminal plasma of normal (n19), oligozoospermic (n11), azoospermic (n12), oligoasthenozoospermic (n19), and asthenozoospermic (n17) subjects was estimated by using atomic absorption spectrophotometer. The concentration of iron in normal seminal plasma varied from 265 to 365 mg%. The source of iron in seminal plasma seems to be the adnexal glands and not spermatozoa, as azoospermic semen also contained it. A statistically highly significant difference was seen when normal was compared with azoospermia and with asthenozoospermia. The necessary average wastage of iron through semen is calculated as 2.52 mg/day. This value is highly variable according to the seminal volume and frequency of ejaculation.