Follicle-stimulating hormone stimulates TNF production from immune cells to enhance osteoblast and osteoclast formation

Declining estrogen production after menopause causes osteoporosis in which the resorption of bone exceeds the increase in bone formation. We recently found that mice deficient in the beta-subunit of follicle-stimulating hormone (FSHbeta) are protected from bone loss despite severe estrogen deficiency. Here we show that FSHbeta-deficient mice have lowered TNFalpha levels. However, TNFalpha-deficient mice are resistant to hypogonadal bone loss despite having elevated FSH, suggesting that TNFalpha is critical to the effect of FSH on bone mass. We find that FSH directly stimulates TNFalpha production from bone marrow granulocytes and macrophages. We also explore how TNFalpha up-regulation induces bone loss. By modeling the known actions of TNFalpha, we attribute the high-turnover bone loss to an expanded osteoclast precursor pool, together with enhanced osteoblast formation. TNFalpha inhibits osteoblastogenesis in the presence of ascorbic acid in culture medium, but in its absence this effect becomes stimulatory; thus, ascorbic acid reverses the true action of TNFalpha. Likewise, ascorbic acid blunts the effects of TNFalpha in stimulating osteoclast formation. We propose that hypogonadal bone loss is caused, at least in part, by enhanced FSH secretion, which in turn increases TNFalpha production to expand the number of bone marrow osteoclast precursors. Ascorbic acid may prevent FSH-induced hypogonadal bone loss by modulating the catabolic actions of TNFalpha.     

Isolated Congenital Tracheobiliary Fistula

Background

Congenital tracheobiliary fistula is a rare developmental anomaly with a persistent communication between the biliary system and the trachea.

Characteristics

A 7-day-old baby with severe respiratory distress and aspiration pneumonia.

Outcome

Tracheobilliary fistula identified on bronchoscopy. Open surgical excision of fistula was followed by improvement.

Message

This condition should be considered in the differential diagnosis of intractable aspiration pneumonia.

     

Impact of brain shift on subcallosal cingulate deep brain stimulation

Background

Deep brain stimulation (DBS) of the subcallosal cingulate (SCC) is an emerging experimental therapy for treatment-resistant depression. New developments in SCC DBS surgical targeting are focused on identifying specific axonal pathways for stimulation that are estimated from preoperatively collected diffusion-weighted imaging (DWI) data. However, brain shift induced by opening burr holes in the skull may alter the position of the target pathways.

Rare tumors of sinonasal track

Objective

To characterize the clinical behavior of rare sinonasal malignancies.

Methods

Clinical data from the cases of rare sinonasal malignancies at Gujarat Cancer and Research Institute during 2001–2007 were extracted. Data for histologic type of tumor, tumor stage and survival were analyzed.

Results

Eighty-nine cases of the non-squamous cell malignancy were identified. The mean patient age was 54 years. In this study, we found minor salivary gland tumor in 31 patients, sarcoma in 19 patients, spindle cell carcinoma (SpCC) in 19 patients, undifferentiated carcinoma in 9 patients, lymphoma in 6 patients and melanoma in 3 patients. Adenoid cystic carcinoma exhibited the best survival rate (3 years survival rate was 77%), whereas melanoma and undifferentiated carcinoma exhibited poor survivals (1 year survival was 25% and 33%, respectively and 3 years survival rate is 0%).

Conclusions

Adenoid cystic carcinoma is the most common squamous cell carcinoma (SCC) of the sinonasal track. Survival for the patients with undifferentiated carcinoma and melanoma involving the sinonasal track is poor.     

Noninvasive methods of detecting fetal anaemia: a systematic review and meta-analysis

Objectives  To estimate in a systematic review of the literature the diagnostic value of ultrasound and Doppler blood flow velocity in the evaluation of fetal anaemia.
Study selection and data extraction  Literature from 2000 to 2008 was identified using MEDLINE and EMBASE, the Cochrane Library and relevant specialist register of the Cochrane Collaboration, and by checking reference lists of known primary studies and review articles. Studies were selected if the accuracy of the fetal ultrasound parameters or Doppler studies of blood flow in the fetal vessels was estimated compared with a reference standard. Data from the selected studies were abstracted as 2 × 2 tables comparing the diagnostic test result with the reference standard. Results were pooled where appropriate. Diagnostic accuracy was expressed as likelihood ratios.
Results  Twenty-five primary studies were identified containing suitable data on middle cerebral artery Doppler peak systolic velocity (MCA-PSV). The largest group of studies whose data could be pooled containing nine studies gave a positive likelihood ratio of 4.30 (95% CI: 2.50 to 7.41) and a negative likelihood ratio of 0.30 (95% CI: 0.13 to 0.69) for 675 cases in detecting severe anaemia in the analysis.
Discussion  Although middle cerebral artery peak systolic velocity Doppler has limited diagnostic accuracy, it remains the gold standard for noninvasive screening of fetal anaemia.     

Curcumin Modulates Efflux Mediated by Yeast ABC Multidrug Transporters and Is Synergistic with Antifungals

Curcumin (CUR), a natural product of turmeric, from rhizomes of Curcuma longa, is a known agent of reversal of drug resistance phenotypes in cancer cells overexpressing ATP-binding cassette (ABC) transporters, viz., ABCB1, ABCG2, and ABCC1. In the present study, we evaluated whether CUR could also modulate multidrug transporters of yeasts that belong either to the ABC family or to the major facilitator superfamily (MFS). The effect of CUR on multidrug transporter proteins was demonstrated by examining rhodamine 6G (R6G) efflux in Saccharomyces cerevisiae cells overexpressing the Candida albicans ABC transporters Cdr1p and Cdr2p (CaCdr1p and CaCdr2p, respectively) and the MFS transporters CaMdr1p and S. cerevisiae Pdr5p. CUR decreased the extracellular concentration of R6G in ABC transporter-expressing cells but had no effect on methotrexate efflux mediated through the MFS transporter CaMdr1p. CUR competitively inhibited R6G efflux and the photolabeling of CaCdr1p by [¹²⁵I]iodoarylazidoprazosin, a drug analogue of the substrate prazosin (50% inhibitory concentration, 14.2 μM). Notably, the mutant variants of CaCdr1p that displayed abrogated efflux of R6G also showed reduced modulation by CUR. Drug susceptibility testing of ABC protein-expressing cells by spot assays and checkerboard tests revealed that CUR was selectively synergistic with drug substrates such as R6G, ketoconazole, itraconazole, and miconazole but not with fluconazole, voriconazole, anisomycin, cycloheximide, or FK520. Taken together, our results provide the first evidence that CUR modulates only ABC multidrug transporters and could be exploited in combination with certain conventional antifungal drugs to reverse multidrug resistance in Candida cells.Overexpression of ATP-binding cassette (ABC) multidrug transporters, including P-glycoprotein (ABCB1), multidrug resistance protein (ABCC1), and mitoxantrone resistance protein (ABCG2), plays a major role in the development of multidrug resistance (MDR) in cancer cells (19). Among the various strategies to combat MDR, blocking the functioning of MDR transporters represents an attractive approach (11). Notably, several functional inhibitors of MDR proteins have been tested, but thus far none are clinically successful, due to the dose-limiting toxic effect of the modulators.To circumvent this problem, extensive efforts have been under way in recent years to identify natural inhibitors of MDR exporters, since natural products have the potential to yield a large number of new drugs. Curcuminoids, from the rhizomes of Curcuma longa, have been reported to reverse the drug resistance phenotype in cancer cells overexpressing ABC transporters, viz., ABCB1, ABCG2, and ABCC1 (2, 4, 5). Curcuminoids blocked the efflux of fluorescent substrates calcein AM, rhodamine 123, and bodipy-FL-vinblastine in MDR cervical carcinoma cell lines overexpressing ABCB1 and the efflux of mitoxantrone and pheophorbide A, mediated by ABCG2, in HEK293 cells (3, 4).In yeasts, including species of the pathogenic genus Candida, upregulation of multidrug transporter genes belonging either to the ABC family or to the major facilitator superfamily (MFS) is frequently observed in cells exposed to drugs and leads to the phenomenon of MDR (29, 31, 32). For clinical isolates of Candida albicans, it has been established that the ABC transporters C. albicans Cdr1p (CaCdr1p) and CaCdr2p and the MFS transporter CaMdr1p are major MDR transporters that contribute to azole resistance. There are compounds, such as FK506, enniatins, milbemycins, synthetic d-octapeptides, cyclosporine, isonitrile, disulfiram, ibuprofen, and unnarmicins (12, 30), that inhibit fungal ABC transporters. Such inhibitors or chemosensitizers probably act directly by affecting substrate binding and transport mediated by MDR efflux proteins.Notably, the effect of curcuminoids on fungal ABC transporters is not known. However, due to functional and structural similarities between ABCB1 and ABC transporters in yeasts, it is very likely that the curcuminoids could act as “reversal agents” of drug resistance in yeasts as well. In this study, we have examined the potency of curcumin (CUR) in modulating the efflux activity of CaCdr1p and have compared it with those of CaCdr2p and Saccharomyces cerevisiae Pdr5p (ScPdr5p). Our results demonstrate that CUR behaves as a specific modulator of rhodamine 6G (R6G) efflux mediated by CaCdr1p, CaCdr2p, and ScPdr5p in S. cerevisiae cells overexpressing these transporters. Notably, CUR had no impact on efflux activity mediated by the MFS transporter CaMdr1p. Furthermore, CUR reversed drug resistance by displaying synergism with selected drugs.     

Fast and slow myosin as markers of muscle regeneration in mangled extremities: a pilot study

Mangled extremities were classically managed by amputation. But over the past few decades, with the advancement in surgical techniques, an increased number of limb salvages have been possible. As muscles usually get damaged in such grievous injuries, a thorough understanding of muscle regeneration may give a better insight into muscle healing in these injuries. Muscles are composed of slow and fast fibers which can be represented by slow and fast myosin, respectively. There are some animal studies which reported differential regeneration of slow and fast muscle fibers during muscle healing. We conducted this pilot study to find out whether the same holds true for muscle healing in mangled extremities also. This pilot study is designed in 15 patients with lower limb mangled extremities presenting to trauma center of PGIMER, Chandigarh, who were operated within 24 h of injury to see whether muscle healing in mangled extremities follows the same pattern. Biopsies were taken during initial surgery conducted within 24 h of injury and on the 7th day of injury when patient was posted again for secondary wound closure procedure or revision amputation. The biopsy samples were subjected to histopathological and immunohistochemistry examination using antibodies against fast and slow myosin. We found that the regenerating muscle fibers in the biopsy sample taken on the 7th day of injury showed only slow muscle fibers with the absence of fast muscle fibers when compared with the initial biopsy results showing differential regeneration of slow muscle fibers.