Hearing Loss in Patients of Chronic Renal Failure: A Study of 100 Cases

The purpose of our study was to determine the incidence of hearing loss and to describe the hearing impairment and the possible contributing factors, responsible for sensori neural hearing loss in chronic renal failure (CRF) patients. This was a prospective study carried out on 50 cases of CRF attending otorhinolaryngological services for hearing disturbance and on 50 healthy volunteers for control study, having the same inclusion criteria except (does not suffering with CRF) having normal renal function tests. These volunteers attended the ENT OPD, for oto-rhino-laryngological services but not for hearing problems. 14 (28%) out of 50 cases of CRF had sensori neural hearing loss of moderate to severe degree in the high frequency range which was bilateral and symmetrical, while in control group the incidence of sensorineural hearing loss was only 6%.     

Higher efficacy of sequential therapy with interferon-alpha and lamivudine combination compared to lamivudine monotherapy in HBeAg positive chronic hepatitis B patients

BACKGROUND: Monotherapy with interferon (IFN) or lamivudine is effective in a limited proportion of chronic hepatitis B (CHB) patients. A sequential combination may have better therapeutic effects by sustained viral suppression combined with immunomodulation. AIM: To compare the efficacy of sequential lamivudine and IFN therapy versus lamivudine monotherapy in HBeAg positive CHB patients. PATIENTS AND METHODS: Seventy-five treatment na?ve HBeAg positive patients with histologically proven CHB and alanine aminotransferase (ALT) >1.5 x ULN received lamivudine 100 mg per day for 52 wks with IFN 5 MIU per day added for 16 wks after the first 8 wks (group A, n = 38; age 30 +/- 12 yr; M:F = 35:3) or lamivudine 100 mg per day for 52 wks (group B, n = 37; age 30 +/- 16 yr; M:F = 31:6). Biochemical and virologic responses were assessed at weeks 52 and 76 and analysis was done on intention-to-treat. Serial samples were studied for the emergence of lamivudine-resistant YM552I/VDD mutations by direct sequencing. RESULTS: At week 52, HBeAg loss occurred in 15 (39.5%) in group A and 14 (37.8%) in group B (p= 1.00). HBeAg loss, anti-HBe appearance, and undetectable DNA levels were seen in 26.3% and 13.5% (p= 0.249), respectively. Nine of 10 (90%) patients in group A and 1 of 5 (20%) in group B maintained the response through week 76 (p= 0.017). At week 76, 5 additional patients in group A and 3 in group B further achieved the primary end point and the overall HBeAg loss was observed in 44.7% and 18.9% (p= 0.025) and HBeAg loss, anti-HBe appearance, and undetectable hepatitis B virus (HBV) DNA levels in 36.8% and 10.8% in group A and group B, respectively (p= 0.026). At week 76, undetectable HBV DNA was seen in 39.5% and 16.2% in groups A and B, respectively (p= 0.039). Normal ALT was seen in 47.7% and 40.5% at week 52 (p= 0.489) and ALT was normal in 39.5% and 13.5% at week 76 (p= 0.018) in groups A and B, respectively. YM552I/VDD-resistant mutants emerged in 6 of 38 (15.5%) patients in group A, and 3 of 37 (8.1%) in group B (p= ns). The rate of histological improvement was comparable in the two groups. CONCLUSIONS: Our results demonstrate that sequential therapy is superior to lamivudine monotherapy in achieving sustained seroconversion, ALT normalization, and HBV DNA loss. Compared to 80% with sequential therapy, only 20% Indian patients with CHB did not relapse after stopping lamivudine monotherapy.     

Evaluation of the antimicrobial, antioxidant, and anti-inflammatory activities of hydroxychavicol for its potential use as an oral care agent

Hydroxychavicol isolated from the chloroform extraction of aqueous extract of Piper betle leaves showed inhibitory activity against oral cavity pathogens. It exhibited an inhibitory effect on all of the oral cavity pathogens tested (MICs of 62.5 to 500 μg/ml) with a minimal bactericidal concentration that was twofold greater than the inhibitory concentration. Hydroxychavicol exhibited concentration-dependent killing of Streptococcus mutans ATCC 25175 up to 4× MIC and also prevented the formation of water-insoluble glucan. Interestingly, hydroxychavicol exhibited an extended postantibiotic effect of 6 to 7 h and prevented the emergence of mutants of S. mutans ATCC 25175 and Actinomyces viscosus ATCC 15987 at 2× MIC. Furthermore, it also inhibited the growth of biofilms generated by S. mutans and A. viscosus and reduced the preformed biofilms by these bacteria. Increased uptake of propidium iodide by hydroxychavicol-treated cells of S. mutans and A. viscosus indicated that hydroxychavicol probably works through the disruption of the permeability barrier of microbial membrane structures. Hydroxychavicol also exhibited potent antioxidant and anti-inflammatory activities. This was evident from its concentration-dependent inhibition of lipid peroxidation and significant suppression of tumor necrosis factor alpha expression in human neutrophils. Its efficacy against adherent cells of S. mutans in water-insoluble glucan in the presence of sucrose suggests that hydroxychavicol would be a useful compound for the development of antibacterial agents against oral pathogens and that it has great potential for use in mouthwash for preventing and treating oral infections.     

Prognostic value of SPECT myocardial perfusion imaging in patients with elevated cardiac troponin I levels and atypical clinical presentation.

BACKGROUND: We determined the prognostic value of myocardial perfusion imaging (MPI) in patients with atypical clinical presentations and unexpected elevation of cardiac troponin I (cTnI) levels. METHODS AND RESULTS: In 156 consecutive patients with atypical presentations for acute coronary syndromes (ACS) and elevated cTnI levels undergoing MPI within 30 days, rates of all-cause mortality (100% follow-up; median follow-up, 611 days) and 6-month cardiac death and nonfatal myocardial infarction (96% follow-up; median follow-up, 167 days) were determined. The mean age of the patients was 68 +/- 14 years. The majority of the study cohort (96%) was at low to intermediate clinical risk for ACS (Thrombolysis in Myocardial Infarction score for unstable angina/non-ST-segment elevation myocardial infarction <5). The overall event rate was high, with 45 deaths (28.8%). There were 13 cardiac deaths/nonfatal myocardial infarctions in 6 months (8.3%). A normal MPI result was associated with a high event-free survival rate, whereas an abnormal MPI result was associated with a 3-fold and 7-fold higher risk of all-cause mortality and 6-month cardiac events, respectively. An abnormal MPI result was an independent predictor of all-cause death. CONCLUSIONS: In patients with cTnI elevation and a low to intermediate risk for ACS, a normal MPI result portends a good prognosis. Patients with abnormal MPI results have a higher 6-month cardiac event rate and a worse survival rate.     

Elevated level of interleukin-6 predicts organ failure and severe disease in patients with acute pancreatitis

BACKGROUND AND AIM: Cytokines play an important role in the pathogenesis of acute pancreatitis (AP). The aim of the present paper was to study the profile of anti- and proinflammatory cytokines in AP and to determine their predictive value for severity of AP, organ failure and mortality. METHODS: Consecutive patients with AP were included in the study. Cytokines were measured in those patients who presented within the first 72 h of the onset of AP. Plasma levels of proinflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-Ibeta, IL-6 and anti-inflammatory cytokine IL-10 were measured on days 1, 3, 7 and 14 of AP. RESULTS: Of 108 patients, 30 presented within 72 h of the onset (mean age 40.27 +/- 13.89 years; 22 males). Of the 30 patients, 13 (43.3%) had severe and 17 (56.7%) had mild pancreatitis. Eleven (36.7%) patients developed organ failure and three died. The level of IL-6 on day 3 was significantly higher in severe pancreatitis than in mild pancreatitis (146.29 +/- 57.53 pg/mL vs 91.42 +/- 71.65 pg/mL; P = 0.04) and was significantly higher in patients who developed organ failure compared with those who did not (161.59 +/- 53.46 pg/mL vs 88.16 +/- 65.50 pg/mL; P = 0.004). At a cut-off value of 122 pg/mL on day 3, IL-6 predicted organ failure and severe pancreatitis with a sensitivity and specificity of 81.8% and 77.7%, respectively. TNF-alpha and IL-10 were detectable only in one-third of patients and were not related to the severity of pancreatitis, while Il-1beta was not detectable. CONCLUSION: Elevated levels of IL-6 predicted organ failure and severe pancreatitis and suggested its pathophysiological significance in AP.     

Mycobacterium tuberculosis DosS is a redox sensor and DosT is a hypoxia sensor

A fundamental challenge to the study of oxidative stress responses of Mycobacterium tuberculosis (Mtb) is to understand how the protective host molecules are sensed and relayed to control bacilli gene expression. The genetic response of Mtb to hypoxia and NO is controlled by the sensor kinases DosS and DosT and the response regulator DosR through activation of the dormancy/NO (Dos) regulon. However, the regulatory ligands of DosS and DosT and the mechanism of signal sensing were unknown. Here, we show that both DosS and DosT bind heme as a prosthetic group and that DosS is rapidly autooxidized to attain the met (Fe3+) form, whereas DosT exists in the O2-bound (oxy) form. EPR and UV-visible spectroscopy analysis showed that O2, NO, and CO are ligands of DosS and DosT. Importantly, we demonstrate that the oxidation or ligation state of the heme iron modulates DosS and DosT autokinase activity and that ferrous DosS, and deoxy DosT, show significantly increased autokinase activity compared with met DosS and oxy DosT. Our data provide direct proof that DosS functions as a redox sensor, whereas DosT functions as a hypoxia sensor, and that O2, NO, and CO are modulatory ligands of DosS and DosT. Finally, we identified a third potential dormancy signal, CO, that induces the Mtb Dos regulon. We conclude that Mtb has evolved finely tuned redox and hypoxia-mediated sensing strategies for detecting O2, NO, and CO. Data presented here establish a paradigm for understanding the mechanism of bacilli persistence.     

Phosphorylation-dependent regulation of nuclear localization and functions of integrin-linked kinase

Integrin-linked kinase (ILK) is a phosphorylated protein that regulates physiological processes that overlap with those regulated by p21-activated kinase 1 (PAK1). Here we report the possible role of ILK phosphorylation by PAK1 in ILK-mediated signaling and intracellular translocation. We found that PAK1 phosphorylates ILK at threonine-173 and serine-246 in vitro and in vivo. Depletion of PAK1 decreased the levels of endogenous ILK phosphorylation in vivo. Mutation of PAK1 phosphorylation sites on ILK to alanine reduced cell motility and cell proliferation. Biochemical fractionation, confocal microscopy, and chromatin-interaction analyses of human cells revealed that ILK localizes predominantly in the cytoplasm but also resides in the nucleus. Transfection of MCF-7 cells with point mutants ILK-T173A, ILK-S246A, or ILK-T173A; S246A (ILK-DM) altered ILK localization. Selective depletion of PAK1 dramatically increased the nuclear and focal point accumulation of ILK, further demonstrating a role for PAK1 in ILK translocation. We also identified functional nuclear localization sequence and nuclear export sequence motifs in ILK, delineated an apparently integral role for ILK in maintaining normal nuclear integrity, and established that ILK interacts with the regulatory region of the CNKSR3 gene chromatin to negatively modulate its expression. Together, these results suggest that ILK is a PAK1 substrate, undergoes phosphorylation-dependent shuttling between the cell nucleus and cytoplasm, and interacts with gene-regulatory chromatin.     

Daratumumab,bortezomib and dexamethasone at first relapse for patients with multiple myeloma: A real-world multicentre UK retrospective analysis

Daratumumab, bortezomib and dexamethasone (DVd) is approved for patients with relapsed multiple myeloma following the CASTOR phase 3 clinical trial. This retrospective multicentre analysis assesses the overall response rate (ORR) and progression-free survival (PFS) in routine clinical practice for patients at first relapse treated with DVd incorporating weekly bortezomib. Data were collected from 296 sequential patients treated across 15 UK centres. After a median follow-up of 21 months, the ORR was 82% (26% partial response, 56% very good partial response or better) and the median PFS was 16 months [95% confidence interval (CI) 12–20 months]. Results were similar regardless of prior lenalidomide exposure. The median time to next treatment was 20 months (95% CI 15–25 months) and the estimated overall survival at two years was 74%. Patients with high-risk features (by cytogenetics, International Staging System or extramedullary disease) and those treated within 18 months of initiation of progression-free treatment, or within 12 months of autologous stem cell transplant, had significantly inferior outcomes. The grade 2 and 3 peripheral neuropathy rate was 7%. DVd with weekly bortezomib was effective in a heterogenous real-world population at first relapse with a low rate of peripheral neuropathy. However, high-risk patients had inferior outcomes and should be considered for alternative treatments.