An update of proliferative glomerulonephritis with monoclonal immunoglobulin deposits.

As aging increases, monoclonal gammopathy is becoming more common and monoclonal gammopathy of renal significance (MGRS) is gaining attention due to frequent renal involvement. Within MGRS, proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is a special category. The disease was first described in 2004 and the research history on it is relatively short. Compared with other MGRS, the detection rate of circulating clones is lower in patients with PGNMID, which is easy to miss and misdiagnose in clinical work. In this review, the etiology and clinical features of PGNMID are discussed. It is noted that PGNMID is associated not only with MGRS, but also with malignancy, infection and other factors. PGNMID is not a disease exclusive to the elderly-young people can also develop this disease. Due to the low detection rate of circulating clones in most patients, confirmation of the disease needs to be combined with renal pathology, which emphasizes the importance of completing light and heavy chain subtype staining. Treatment options for patients with PGNMID differ by etiology. For MGRS-associated PGNMID, the current treatment is primarily empirical and more research evidence is needed to fill the treatment gap.

Discovery of an Orally Active and Long-Acting DPP-IV Inhibitor through Property-Based Optimization with an in Silico Biotransformation Prediction Tool.

Long-acting dipeptidyl peptidase IV inhibitors have emerged as promising molecules for interventions for type 2 diabetes. Once weekly dosing brings greater patient compliance and more stable glycemic control. Starting from our previous highly potent compound with a thienoprimidine scaffold, which is unfortunately severely hit by hepatic biotransformation, a lead compound was rapidly generated by drawing on the experience of our previously discovered long-acting compounds with pyrrolopyrimidine scaffold. With the aid of an in silico biotransformation prediction tool, (R)-2-((2-(3-aminopiperidin-1-yl)-4-oxo-6-(pyridin-3-yl)thieno[3,2-d]pyrimidin-3(4H)-yl)methyl)-4-fluorobenzonitrile was eventually generated and determined to have high potency, a fine pharmacokinetic profile, and a long-acting in vivo efficacy.

Spectrum and prognosis of renal histopathological lesions in 56 Chinese patients with rheumatoid arthritis with renal involvement.

The objective of the study was to evaluate the characteristics and prognosis of 56 patients with rheumatoid arthritis (RA)-associated renal involvement by retrospective review of their renal biopsy specimens. Included in this cross-sectional study were 56 RA patients with renal involvement, in whom renal biopsy was performed to analyze the histological pattern and renal prognosis. IgA nephropathy (IgAN) was detected in 48.2% of the 56 included patients as the most common renal histological pattern, followed by membranous nephropathy (MN) in 23.2% cases, focal segmental glomerular sclerosis (FSGS) in 19.6% cases, chronic interstitial nephritis (CIN) in 5.4% cases, membranoproliferative glomerulonephritis (MPGN) in 1.8% cases, and non-IgA mesangial proliferative glomerulonephritis in 1.8% cases. No significant relationship was observed between the histopathologic type and the RA duration, joint deformity or treatment. Renal dysfunction was mainly found in IgAN patients, and MN occurred more frequently in older patients. Renal function decline occurred in two IgAN patients, one with FSGS and the other with MPGN. Another CIN patient progressed to dialysis during the follow-up period. The patients with renal function decline had a significantly higher level of serum creatinine at presentation. The high percentage of glomeruli sclerosis and interstitial fibrosis/tubular atrophy was also related to renal function decline. IgAN was the major RA-associated renal histological lesion in our series. Renal biopsy can provide useful information about the histological pattern and renal prognosis and therefore should be considered in RA patients with renal involvement.

BMS-345541 sensitizes MCF-7 breast cancer cells to ionizing radiation by selective inhibition of homologous recombinational repair of DNA double-strand breaks.

Our study was to elucidate the mechanisms whereby BMS-345541 (BMS, a specific IκB kinase ß inhibitor) inhibits the repair of DNA double-strand breaks (DSBs) and evaluate whether BMS can sensitize MCF-7 breast cancer cells (MCF-7 cells) to ionizing radiation (IR) in an apoptosis-independent manner. In this study, MCF-7 cells were exposed to IR in vitro and in vivo with or without pretreatment of BMS. The effects of BMS on the repair of IR-induced DSBs by homologous recombination (HR) and non-homologous end-joining (NHEJ) were analyzed by the DR-GFP and EJ5-GFP reporter assays and IR-induced γ-H2AX, 53BP1, Brca1 and Rad51 foci assays. The mechanisms by which BMS inhibits HR were examined by microarray analysis and quantitative reverse transcription PCR. The effects of BMS on the sensitivity of MCF-7 cells to IR were determined by MTT and clonogenic assays in vitro and tumor growth inhibition in vivo in a xenograft mouse model. The results showed that BMS selectively inhibited HR repair of DSBs in MCF-7 cells, most likely by down-regulation of several genes that participate in HR. This resulted in a significant increase in the DNA damage response that sensitizes MCF-7 cells to IR-induced cell death in an apoptosis-independent manner. Furthermore, BMS treatment sensitized MCF-7 xenograft tumors to radiation therapy in vivo in an association with a significant delay in the repair of IR-induced DSBs. These data suggest that BMS is a novel HR inhibitor that has the potential to be used as a radiosensitizer to increase the responsiveness of cancer to radiotherapy.

An Src-protein tyrosine kinase inhibitor to reduce cisplatin ototoxicity while preserving its antitumor effect.

Ototoxicity remains a major dose-limiting side effect of cisplatin. The current studies were carried out to evaluate the effectiveness of a novel Src-protein tyrosine kinase inhibitor in protecting the ear from cisplatin ototoxicity without compromising cisplatin's antitumor effects. The Src inhibitor has been shown to be effective in protecting the ear from noise-induced hearing loss. Three studies were carried out to determine whether this compound has otoprotective activity in rats treated with cisplatin. The first two studies used the Src inhibitor as a cotreatment with single doses of cisplatin in Fischer 344/NHsd rats and nude rats, respectively. Cochlear damage was assessed by auditory brainstem response threshold shifts and outer hair cell loss. The third study was carried out in nude rats with implanted HT-29 tumors, and the Src inhibitor was administered as a cotreatment with a lower dose of cisplatin. Cochlear damage and changes in tumor volume were assessed in the third study. In the first two studies, cotreatment with the Src inhibitor reduced cisplatin-induced hearing loss significantly. In the third study, little hearing loss was induced because of the use of a lower dose of cisplatin. However, cotreatment with the Src inhibitor did not exert a negative effect on cisplatin's slowing of tumor growth in the treated rats. The findings suggest that the Src inhibitor may provide an effective cotreatment with cisplatin to reduce cisplatin's ototoxicity, without compromising its antitumor capability.

Unmyelinated auditory type I spiral ganglion neurons in congenic Ly5.1 mice.

With the exception of humans, the somata of type I spiral ganglion neurons (SGNs) of most mammalian species are heavily myelinated. In an earlier study, we used Ly5.1 congenic mice as transplant recipients to investigate the role of hematopoietic stem cells in the adult mouse inner ear. An unanticipated finding was that a large percentage of the SGNs in this strain were unmyelinated. Further characterization of the auditory phenotype of young adult Ly5.1 mice in the present study revealed several unusual characteristics, including 1) large aggregates of unmyelinated SGNs in the apical and middle turns, 2) symmetrical junction-like contacts between the unmyelinated neurons, 3) abnormal expression patterns for CNPase and connexin 29 in the SGN clusters, 4) reduced SGN density in the basal cochlea without a corresponding loss of sensory hair cells, 5) significantly delayed auditory brainstem response (ABR) wave I latencies at low and middle frequencies compared with control mice with similar ABR threshold, and 6) elevated ABR thresholds and deceased wave I amplitudes at high frequencies. Taken together, these data suggest a defect in Schwann cells that leads to incomplete myelinization of SGNs during cochlear development. The Ly5.1 mouse strain appears to be the only rodent model so far identified with a high degree of the "human-like" feature of unmyelinated SGNs that aggregate into neural clusters. Thus, this strain may provide a suitable animal platform for modeling human auditory information processing such as synchronous neural activity and other auditory response properties.

The effects of acoustic environment after traumatic noise exposure on hearing and outer hair cells.

Previous studies reported that exposure to non-traumatic level sounds after traumatic noise exposure reduced the degree of noise-induced hearing loss and hair cell stereocilia damage. The current study investigated the effects of a 3-day post-noise acoustic environment on the degree of noise-induced hearing loss and cochlear damage. Female chinchillas were exposed to traumatic continuous noise (4 kHz octave-band noise) at 107 dB SPL for 1h and then placed in either an augmented acoustic environment (AAE) or deprived acoustic environment (DAE) for 3 days. The AAE group was exposed to a broad-band noise (4-20 kHz) at 80 dB SPL and the DAE animals were fit with conventional earplugs to minimize the level of acoustic stimulation. Auditory brainstem responses (ABRs) were recorded before and 3 days after the traumatic noise exposure. The AAE group showed a significantly lower average threshold shift at the frequencies of 4 and 8 kHz (p<0.01). Correspondingly, significantly fewer missing and dying outer hair cells (OHCs) were observed in the AAE group than in the DAE group. Although the cochlear reduced and oxidized glutathione levels (GSH and GSSG, respectively) were essentially the same in two groups at day 3, significant correlations were found between GSSG levels and mean ABR threshold shift (1-16 kHz) in the AAE group; as well as GSSG and percentage of total OHC loss in the DAE group. The results suggest that post-noise acoustic environment influenced the degree of hearing loss and OHC deterioration after traumatic noise exposure.

[Expression of antisecretory factor and aquaporin 1, 2 in the rat inner ear and their interaction].

OBJECTIVE: To study the interaction among aquaporin1 (AQP), aquaporin2 (AQP2) and antisecretory factor( AF) , and their expression in the rat inner ear for furthur understanding of Meniere' s disease. METHODS: Inner ear tissue section of six healthy male Sprague-Dawley rats was performed and Envision immunochemical staining was applied to detect the expression of AF, AQP1 and AQP2 in the rat inner ear. Vestibular and cochlear tissues of twenty healthy male Sprague-Dawley rats were dissected. Coimmunoprecipitation and Western Blot were used to specifically immunoprecipitate AF protein in the vestibular and cochlear tissues with monoclonal antibodies against AQP1 and polyclonal antibodies antibodies against AQP2 to detect the above precipitate with specific antibodies against AF. RESULTS: (1) AF was widely distributed in the inner ear, such as marginal cells of stria vascularis , five classes of spiral ligament fibrocyte , Reissner's membrane, basilar membrane, ampullar crest and so on with mild or moderate staining. In addition, round membrane was moderately or markedly stained. Positive immunostaining was found in the cochlear spiral ganglion, vestibular nerve and cochlear nerve. AQP1 was distributed in the intermediate cells in stria vascularis, type III fibrocyte of spiral ligament, basilar membrane and round membrane with moderate to marked degree of immunostaining intensity. AQP2 was mainly localized to the type II, IV, and V fibrocyte of spiral ligament, with moderate to marked degree of immunostaining intensity, round membrane was weakly stained. (2) No band was observed in the control and a single immunoreactive band of 60 000 was observed, which was equal to the molecular mass of AF. CONCLUSIONS: (1) AF, AQP1 and AQP2 have its individual specific localization in the rat inner ear, which was close to the parts of endolymph, so regulating water of the endolymph may be possible. (2) The range of localization of AF overlapped the distribution of AQP1 and AQP2. The results showed the existence of AF protein in the immunoprecipitate using co-immunoprecipitation combined with Western Blot. It suggested that the interaction between AQP1, AQP2 and AF might be possible.

Triple semicircular canal occlusion in guinea pigs with endolymphatic hydrops.

HYPOTHESIS: Triple semicircular canal occlusion will eliminate rotatory stimulation to the vestibular peripheral system (as it blocks endolymphatic fluid movement) and therefore release rotatory vertigo attack. This surgery is safe in ears with endolymphatic hydrops. BACKGROUND: Semicircular canal occlusion has been used as an alternative treatment of intractable benign paroxysmal positional vertigo with varied success. Triple semicircular canal occlusion in animal models blocks the responses of the semicircular canals to rotation and spares cochleae and the otolithic apparatus. This result suggests that triple semicircular canal occlusion is a prospective method in vertigo management for patients with Ménière's disease. However, the effectiveness and safety of triple semicircular canal occlusion has not been fully evaluated in ears with endolymphatic hydrops. METHODS: Endolymphatic hydrops was established in 20 guinea pigs by endolymphatic sac obliteration. Triple semicircular canal occlusion was performed in 12 of them 120 days after endolymphatic hydrops surgery, whereas 8 others were killed for morphologic observation to confirm endolymphatic hydrops. Auditory and vestibular functions were monitored from the time before endolymphatic hydrops until 1 month after triple semicircular canal occlusion. Endolymphatic hydrops and canal occlusion were confirmed by morphologic observation. RESULTS: Successful establishment of endolymphatic hydrops was indicated by mild elevation of the auditory brainstem response threshold and tentative asymmetry in nystagmus. Endolymphatic hydrops was confirmed by cochlear morphology in all eight animals that were killed 120 days after endolymphatic hydrops surgery. After triple semicircular canal occlusion, all 12 animals showed spontaneous nystagmus with a slow component toward the side that had been operated on, head tilt, rotated walking, and tentative asymmetry in rotatory nystagmus. The static symptoms disappeared within 1 month after triple semicircular canal occlusion. Caloric nystagmus was only slightly reduced after endolymphatic hydrops as compared with the contralateral ears but could not be elicited at all after triple semicircular canal occlusion. No significant elevation in auditory brainstem response threshold was found after triple semicircular canal occlusion. The canal occlusion and endolymphatic hydrops were confirmed in all surgical ears. CONCLUSION: Triple semicircular canal occlusion is effective for eliminating the response of semicircular canals to rotation and caloric stimulation and is safe in ears with endolymphatic hydrops. Also, the static compensation to the disequilibrium is quick and complete. These results suggest that triple semicircular canal occlusion should be an option for controlling rotatory vertigo in Ménière's disease.