New therapeutic opportunities for hepatitis C based on small RNA

Hepatitis C virus (HCV) infection is one of the major causes of chronic liver disease, including cirrhosis and liver cancer and is therefore, the most common indication for liver transplantation. Conventional antiviral drugs such as pegylated interferon-alpha, taken in combination with ribavirin, represent a milestone in the therapy of this disease. However, due to different viral and host factors, clinical success can be achieved only in approximately half of patients, making urgent the requirement of exploiting alternative approaches for HCV therapy. Fortunately, recent advances in the understanding of HCV viral replication and host cell interactions have opened new possibilities for therapeutic intervention. The most recent technologies, such as small interference RNA mediated gene-silencing, anti-sense oligonucleotides (ASO), or viral vector based gene delivery systems, have paved the way to develop novel therapeutic modalities for HCV. In this review, we outline the application of these technologies in the context of HCV therapy. In particular, we will focus on the newly defined role of cellular microRNA (miR-122) in viral replication and discuss its potential for HCV molecular therapy.     

Prevention of glucocorticoid induced osteoporosis with alendronate or alfacalcidol: relations of change in bone mineral density, bone markers, and calcium homeostasis

OBJECTIVE: To explore the relation of changes in measures of bone turnover and changes in bone mineral density (BMD) of the lumbar spine and total hip over 18 months in a double-blinded, randomized trial, comparing the effect of alfacalcidol (101 patients) versus alendronate (100 patients) on BMD in patients who recently started treatment with glucocorticoids for various rheumatic diseases. METHODS: Associations between changes in serum procollagen type I C-propeptide (P1CP), fasting urine N-terminal telopeptide of type I collagen (NTx), serum calcium, parathyroid hormone (PTH), osteocalcin, and change from baseline in BMD over 18 months were explored with regression and correlation analyses. RESULTS: In both treatment groups, there was a statistically significant decrease in NTx. In the alfacalcidol group there was also a significant increase in P1CP and osteocalcin, in contrast to the alendronate group, but BMD in the alfacalcidol decreased versus an increase in the alendronate group (p < 0.001). In neither treatment group were changes in biochemical measures correlated with the change in BMD, with the exception of a negative correlation in the alendronate group between changes in total hip BMD and NTx. Use of alendronate resulted in an increased PTH in 27 patients, but the increase in BMD of these patients was not statistically significantly different compared to patients taking alendronate with normal PTH levels. CONCLUSION: Changes in BMD were not associated with changes in bone measures, with the exception of NTx in the alendronate group. For the patient taking glucocorticoids in clinical practice, the value of serial assessment of bone markers is low; changes in markers are no substitute for changes in BMD. ClinicalTrials.gov number: NCT00138983.     

Differentiating normal myelination from hypoxic-ischemic encephalopathy on T1-weighted MR Images: a new approach

BACKGROUND AND PURPOSE: Hypoxic-ischemic cerebral changes can be difficult to distinguish from normal myelination on T1-weighted images. We hypothesized that comparing signal intensity (SI) of brain structures on T1-weighted images enables differentiation of myelination from hypoxic-ischemic brain damage. MATERIALS AND METHODS: T1-weighted images, obtained in 57 infants aged 1-104 days and born after a gestational age of 35 weeks or older, were retrospectively evaluated. Subjects were assigned to a patient (n = 23, with perinatal hypoxic-ischemic encephalopathy [HIE] stage 2/3) or a control group (n = 34). In each subject, an SI score was assigned to 19 brain structures on the basis of pairwise comparisons with the other 18 structures. In both groups, mean total SI scores were calculated for the 19 structures. Independent samples t tests assessed whether the mean total score of a structure differed significantly between the 2 groups. Logistic regression assessed which comparison was best to distinguish between the groups and to predict the presence of hypoxic-ischemic injury. RESULTS: In patients, mean total SI scores for posterolateral putamen (PP) and peri-Rolandic cortex (PC) were significantly higher (P = .000 for both). Mean total SI scores of the posterior limb of internal capsule (PLIC) and the corona radiata (CR) were significantly lower in patients (P = .000 and 0.005, respectively). Two comparisons (PLIC versus CR, PP versus PC) were best to distinguish patients and controls and to predict absence or presence of HIE (P < .0001). CONCLUSION: SI changes due to hypoxia-ischemia can be differentiated from normal myelination by comparing SI of 4 brain structures on T1-weighted images.     

Lung cancer survival with herbal medicine and vitamins in a whole-systems approach: ten-year follow-up data analyzed with marginal structural models and propensity score methods

Complementary and alternative medicines are used by up to 48% of lung cancer patients but have seen little formal assessment of survival efficacy. In this 10-year retrospective survival study, the authors investigated Pan-Asian medicine + vitamins (PAM+V) therapy in a consecutive case series of all non-small-cell lung cancer patients (n = 239) presenting at a San Francisco Bay Area Chinese medicine center (Pine Street Clinic). They compared short-term treatment lasting the duration of chemotherapy/radiotherapy with long-term therapy continuing beyond conventional therapy. They also compared PAM+V plus conventional therapy with conventional therapy alone, using concurrent controls from the Kaiser Permanente Northern California and California Cancer Registries. They adjusted for confounding with Kaplan-Meier, Cox regression, and newer methods - propensity score and marginal structural models (MSMs), which when analyzing data from observational studies or clinical practice records can provide results comparable with randomized trials. Long-term use of PAM+V beyond completion of chemotherapy reduced stage IIIB deaths by 83% and stage IV by 72% compared with short-term use only for the duration of chemotherapy. Long-term PAM+V combined with conventional therapy reduced stage IIIA deaths by 46%, stage IIIB by 62%, and stage IV by 69% compared with conventional therapy alone. Survival rates for stage IV patients treated with PAM+V were 82% at 1 year, 68% at 2 years, and 14% at 5 years. PAM+V combined with conventional therapy improved survival in stages IIIA, IIIB, and IV, compared with conventional therapy alone. Prospective trials using PAM+V with conventional therapy for lung cancer patients are justified.     

Effects of Appraisal of Sexual Stimuli on Sexual Arousal in Women with and Without Superficial Dyspareunia

This study examined the effects of appraisal of sexual stimuli on sexual arousal in women with superficial dyspareunia (n = 50) and sexually functional women (n = 25). To elicit different appraisals of an erotic film fragment, participants received an instruction prior to viewing it, with a focus on genital pain or on sexual enjoyment. A neutral instruction served as a control condition. Assignment to instruction condition was randomized. Genital arousal (vaginal pulse amplitude) and self-report ratings of affect and genital sensations were obtained in response to the erotic stimulus. As predicted, appraisal of the erotic stimulus affected genital responding, albeit marginally significant. Follow-up tests indicated that women who received the genital pain instruction responded with marginally significant lower genital arousal levels than women who received the sexual enjoyment instruction (d = 0.67). A significant instruction effect for negative affect was found, signifying that negative affect ratings were highest after the genital pain instruction and lowest after the sexual enjoyment instruction (d = 0.80). A marginally significant group by instruction interaction effect was observed for positive affect, indicating that women with dyspareunia reported significantly less positive affect than controls after the sexual enjoyment instruction (d = 1.48). Whereas women with dyspareunia reported overall marginally significant more negative affect than controls (d = 0.48), there were no differences in genital responsiveness between groups. These results provided preliminary evidence for the modulatory effects of appraisal of sexual stimuli on subsequent genital responding and affect in women with and without sexual complaints.     

Second-line drug resistance in multidrug-resistant tuberculosis cases of various origins in the Netherlands

SETTING: The Netherlands. OBJECTIVE: To investigate the frequency of resistance to second-line drugs among multidrug-resistant tuberculosis (MDR-TB) cases and its correlation with patients' geographic origin. DESIGN: Retrospective laboratory database study of multidrug-resistant Mycobacterium tuberculosis complex strains isolated in the Netherlands between January 1993 and October 2007. RESULTS: We found 153 patients with MDR-TB, of whom 18 (12%) were native Dutch. Complete second-line drug susceptibility testing was performed for 131 MDR-TB patients. Resistance to second-line drugs was noted in primary samples of 28 (21%) MDR-TB patients. Resistance to a single second-line drug was most frequent (24/28 [86%]; 9 to prothionamide [PTH], 6 to para-aminosalicylic acid, 4 to amikacin [AMK], 4 to ciprofloxacin and 1 to cycloserine). Four MDR-TB patients had strains resistant to multiple second-line drugs; two were extensively drug-resistant M. bovis. In MDR-TB patients of European and Central Asian origin, resistance to second-line drugs was most frequent and involved the widest range of drugs. PTH resistance was frequent among African and American MDR-TB patients, while AMK resistance was frequent among South-East Asians. CONCLUSION: Resistance to second-line drugs is infrequent among MDR-TB patients in the Netherlands. Most second-line drug resistance is recorded among immigrants, with substantial differences in second-line drug resistance in MDR-TB patients originating from different geographical areas.     

An often unrecognized cause of thunderclap headache: reversible cerebral vasoconstriction syndrome

Thunderclap headache (TCH) can have several causes of which subarachnoid hemorrhage (SAH) is most common and well known. A rare cause of TCH is the reversible cerebral vasoconstriction syndrome (RCVS) which is characterized by a reversible segmental vasoconstriction of the intracranial vessels. We describe two patients with TCH due to RCVS and the probable precipitating factor, namely, cannabis and an anti-migraine drug. In RCVS, cerebrospinal fluid examination is (near) normal, in contrast to SAH and (primary) cerebral vasculitis. Brain MRI may be normal or shows infarction. MRA can demonstrate vasoconstriction of the great arteries, but a normal MRA does not rule out the diagnosis. Caliber changes on cerebral angiography cannot adequately differentiate between RCVS and vasculitis. Calcium-channel antagonists may be a good therapy and repeated transcranial Doppler ultrasonography can be a reliable non-invasive investigation to monitor the effect of treatment and demonstrate reversibility of the vasoconstriction.