Focal Segmental Membranoproliferative Glomerulonephritis: A Histological Variant of Denys-Drash Syndrome.

Introduction: Denys-Drash Syndrome (DDS) consists of a triad of pseudohermaphroditism, Wilms'tumor and nephropathy. This condition may manifest as a complete triad or in an incomplete form; with either one or a combination of the above features. The characteristic glomerular abnormality in DDS is diffuse mesangial sclerosis (DMS).Case report: We report two cases of DDS with focal membranoproliferative glomerulonephritis (MPGN). Both of our cases were males with ambiguous genitalia. They had a similar heterozygous germline mutation in exon 9 of WT1, c.1180C>T, p.R394W; a known mutation hotspot for DDS. Case 1 had nephropathy at the age of 4 years and Case 2 at 2.5 years with different rates of progression to end-stage renal failure. Conclusion: Our findings, in combination with other reports, illustrate the clinicopathological heterogeneity of DDS. There are no universal recommendations for optimal management of patients with DDS due to the inability to accurately predict affected individuals' progress.

Elective neck dissection versus observation for early-stage oral squamous cell carcinoma: Systematic review and meta-analysis.

INTRODUCTION: Oral squamous cell carcinoma (OSCC) is the seventh most common cancer globally, and has been identified as a growing health concern. This study aims to evaluate the current literature comparing elective neck dissection to observation in the treatment of early-stage tongue SCC, focusing on nodal recurrence, overall survival, disease specific survival statistics from randomised controlled trials comparing the two interventions. METHODS: Systematic review and meta-analysis was conducted according to PRISMA guidelines. The odds ratio (OR) was used as a summary statistic. RESULTS: From 8 studies, there was a total of 372 cases of recurrence, 98 (15.1%) in END group and 274 (41.5%) in the Observation group. There was a significantly lower rate of recurrence in the END group compared to observation (OR 0.25, 95% CI 0.16-0.39, I2 = 54%, P < 0.00001). END was associated with higher overall survival rates when compared with observation (OR 1.95, 95% CI 1.40-2.73, I2 = 14%, P < 0.0001). END was also associated with higher disease-specific survival compared with observation (OR 1.88, 95% CI 1.21-2.93), I2 = 47%, P = 0.005), with no significant heterogeneity noted. CONCLUSIONS: END was associated with significantly lower recurrence rates and higher overall and disease-specific survival compared to a conservative observation approach in early-stage oral SCC with clinically N0 neck.

Frequent occurrence of gastric cancer in Asian kindreds with Li-Fraumeni syndrome.

Type of cancer and age of onset in individuals with inherited aberrations in the tumour suppressor gene TP53 are variable, possibly influenced by genetic modifiers and different environmental exposure. Since 2009, the modified Chompret criteria (MCC) have been used to identify individuals for TP53 mutation screening. Using the TP53 mutation database maintained by the International Agency for Research on Cancer (IARC), we investigated if the MCC, mainly developed for a Caucasian population, was also applicable in Asia. We identified several differences in Asian families compared with similar Caucasian cohorts, suggesting that identification and management of Li-Fraumeni syndrome in Asia do not completely mirror that of North America and Western Europe. Early gastric cancer (<40 years) may be considered a new addition to the MCC especially for Asian families.

Immunomodulatory effects of H.P. Acthar Gel on B cell development in the NZB/W F1 mouse model of systemic lupus erythematosus.

H.P. Acthar Gel® (Acthar) is a highly purified repository gel preparation of adrenocorticotropic hormone (ACTH1-39), a melanocortin peptide that can bind and activate specific receptors expressed on a range of systemic lupus erythematosus (SLE)-relevant target cells and tissues. This study was performed to evaluate the effects of Acthar in a mouse model of SLE, using an F1 hybrid of the New Zealand Black and New Zealand White strains (NZB/W F1). Twenty-eight week old NZB/W F1 mice with established autoimmune disease were treated with Acthar, Placebo Gel (Placebo), or prednisolone and monitored for 19 weeks. Outcomes assessed included disease severity (severe proteinuria, ≥ 20% body weight loss, or prostration), measurement of serial serum autoantibody titers, terminal spleen immunophenotyping, and evaluation of renal histopathology. Acthar treatment was linked with evidence of altered B cell differentiation and development, manifested by a significant reduction in splenic B cell follicular and germinal center cells, and decreased levels of circulating total and anti-double-stranded DNA (IgM, IgG, and IgG2a) autoantibodies as compared with Placebo. Additionally, Acthar treatment resulted in a significant decrease of proteinuria, reduced renal lymphocyte infiltration, and attenuation of glomerular immune complex deposition. These data suggest that Acthar diminished pathogenic autoimmune responses in the spleen, peripheral blood, and kidney of NZB/W F1 mice. This is the first preclinical evidence demonstrating Acthar's potential immunomodulatory activity and efficacy in a murine model of systemic lupus erythematosus.

Total shoulder replacement for osteoarthritis in patients 80 years of age and older.

This study was performed to review the safety and outcome of total shoulder replacements in patients who are > or = 80 years of age. A total of 50 total shoulder replacements in 44 patients at a mean age of 82 years (80 to 89) were studied. Their health and shoulder status, the operation and post-operative course were analysed, including pain, movement, patient satisfaction, medical and surgical complications, radiographs, the need for revision surgery, and implant and patient survival. A total of 27 patients had an ASA classification of III or IV and medical abnormalities were common. Of the 13 shoulders with bony deficiency of the glenoid, nine required grafting. The duration of hospital stay was prolonged and blood transfusions were common. There were no peri-operative deaths. The mean follow-up was for 5.5 years (2 to 12). Pain was significantly reduced (p < 0.001) and movement improved in active elevation and both external and internal rotation (p < 0.001). Using the Neer scale for assessing outcome, 40 (80%) shoulders had an excellent or satisfactory result. There were medical or surgical complications in 17 cases. Four shoulders developed radiological evidence of loosened glenoid components, and three of these had a poor outcome. Three other shoulders required revision, two for instability. By the time of this review 39 of the patients had died from unrelated causes at a mean of 7.5 years (0.8 to 16.4) after surgery. Total shoulder replacement is a relatively effective treatment in this elderly group of patients. However, there is a requirement for more intense patient care in the peri-operative period, and non-fatal medical or surgical complications are common. Most of these elderly patients will have a comfortable functional shoulder for the rest of their lives.

The core and hip in soccer athletes compared by gender.

Gender differences in hip and core strength and range of motion may contribute to the gender based variance in injury risk. This study was designed to test the primary hypothesis that hip and core strength, flexibility and lower extremity dynamic alignment differ in male and female soccer athletes. Ninety-eight collegiate soccer players (54 male, 44 female) participated in this study. Athletes were evaluated for hip range of motion, and hip and abdominal strength. Both male and female soccer players demonstrated limited hip rotation, with less hip internal rotation in males (p<0.0001), and poor abdominal core control, although the males are stronger (p=0.02). Overall hip ROM is shifted towards internal rotation in females compared to males. Female soccer players also have a significant side-to-side disparity in hip abductor strength (p<0.0001), not present in males. The shift in hip ROM towards internal rotation combined with the hip abductor imbalance may be associated with a position of ACL risk with internally rotated hips and valgus knees in female soccer players. Limitations in hip and core strength and range of motion may play a role in the disparity between the male and female rate of ACL injury.

Mice with conditional inactivation of fibroblast growth factor receptor-2 signaling in oligodendrocytes have normal myelin but display dramatic hyperactivity when combined with Cnp1 inactivation.

Fibroblast growth factor receptors (Fgfr) comprise a widely expressed family of developmental regulators implicated in oligodendrocyte (OL) maturation of the CNS. Fgfr2 is expressed by OLs in myelinated fiber tracks. In vitro, Fgfr2 is highly upregulated during OL terminal differentiation, and its activation leads to enhanced growth of OL processes and the formation of myelin-like membranes. To investigate the in vivo function of Fgfr2 signaling by myelinating glial cells, we inactivated the floxed Fgfr2 gene in mice that coexpress Cre recombinase (cre) as a knock-in gene into the OL-specific 2',3'-cyclic nucleotide phosphodiesterase (Cnp1) locus. Surprisingly, no obvious defects were detected in brain development of these conditional mutants, including the number of OLs, the onset and extent of myelination, the ultrastructure of myelin, and the expression level of myelin proteins. However, unexpectedly, a subset of these conditional Fgfr2 knock-out mice that are homozygous for cre and therefore are also Cnp1 null, displayed a dramatic hyperactive behavior starting at approximately 2 weeks of age. This hyperactivity was abolished by treatment with dopamine receptor antagonists or catecholamine biosynthesis inhibitors, suggesting that the symptoms involve a dysregulation of the dopaminergic system. Although the molecular mechanisms are presently unknown, this novel mouse model of hyperactivity demonstrates the potential involvement of OLs in neuropsychiatric disorders, as well as the nonpredictable role of genetic interactions in the behavioral phenotype of mice.

Epidural analgesia in primigravidae in spontaneous labour at term: a prospective study.

OBJECTIVES: To prospectively study the intervention rate, duration of labour, malpositions, fetal outcome, maternal satisfaction, voiding complications and adverse events in healthy primigravidae in spontaneous labour at term following epidural analgesia. METHODS: A prospective randomized study involving 55 patients in the epidural group and 68 in the control pethidine--inhalational entonox group. RESULTS: There were significantly more obstetric interventions (instrumental deliveries) in the epidural group (p < 0.01). The total duration of labour and the duration of the second stage was prolonged in the epidural group (p < 0.01). There were more malpositions at the second stage of labour in the epidural group (p < 0.02). There were no differences in fetal outcome (Apgar scores and Special Care Nursery admissions). Patients in the epidural group were consistently happier with their method of pain relief (p < 0.01). Two patients required blood patches while another 2 patients had persistent backache post epidural analgesia. CONCLUSION: Epidural analgesia in primigravidae in spontaneous labour at term led to an increased instrumental delivery rate, prolonged duration of labour, greater rate of malpositions in the second stage, increased oxytocin requirements but with no difference in fetal outcomes but with happier mothers as compared to the control group.

Matrix metalloproteinase-9/gelatinase B is required for process outgrowth by oligodendrocytes.

Oligodendrocytes (OLs) extend processes to contact axons as a prerequisite step in myelin formation. As the OL processes migrate toward their axonal targets, they modify adhesion to their substrate, an event that may be regulated by matrix metalloproteinases (MMPs). In the mouse optic nerve, MMP-9/gelatinase B increases during myelin formation. Although tissue inhibitor of metalloproteinase (TIMP)-3 also increases in parallel, the developing optic nerve has focally active MMPs demonstrable by in situ zymography. The distribution of proteolytic activity is similar to that of myelin basic protein, a marker of myelin formation. OLs in culture secrete MMP-9 and express active cell-associated metalloproteinases at the growing tips of their processes. TIMP-1 and a function-perturbing anti-MMP-9 antibody attenuate outgrowth of processes by OLs, indicating a requirement for MMP-9 in process outgrowth. Process reformation is retarded significantly in OLs cultured from MMP-9 null mice, as compared with controls, providing genetic evidence that MMP-9 is necessary for process outgrowth. These data show that MMP-9 facilitates process outgrowth by OLs in vivo and in culture.

Pain during elective caesarean section under epidural anaesthesia: the effect of a 10 degrees head-up tilt position.

One hundred patients scheduled for elective caesarean section under epidural anaesthesia were randomized to have epidural loading doses in either the horizontal or a 10 degrees head-up position. They were assigned to their position only after an initial dose of 4 ml of 0.5% bupivacaine had been given. Ten minutes after this dose they were given 10 ml of 0.5% bupivacaine and 50 microg of fentanyl in their allocated position. Pain during surgery was assessed by the patients using a visual analogue scale and by a blinded anaesthetist. Giving the main dose in the head-up tilt position reduced the incidence of intea-operative pain significantly. The median pain score for the head-up position was zero while the score was two for the horizontal position. The inter-quartile range was 0 to 2 for the head-up tilt position and 0 to 4 for the horizontal position (P<0.05). Position had no significant effect on the blood pressure or Bromage score. A 10 degrees head-up tilt position is useful during the establishment of epidural anaesthesia to reduce the pain experienced by the patient during caesarean section.

Inhibition of HIV-1 replication by combination of a novel inhibitor of TNF-alpha with AZT.

The small molecule S9a was derived from an established tumor necrosis factor-alpha (TNF-alpha) inhibitor (Canventol) by replacement of the isopropylidine group with a phenyl ring. S9a at 10 to 100 nM inhibited HIV production as potently as 3'-azido-3'-deoxythymidine (AZT), an inhibitor of viral reverse transcriptase. Furthermore, S9a and AZT in combination, at noncytoxic concentrations strongly inhibited HIV-1 replication that was more than additive and substantially prolonged the appearance of virus both in acutely infected CD4+ lymphocytes (SupT) in culture and in peripheral blood mononuclear cells (PBMCs) infected with a primary HIV-1 isolate. S9a inhibited TNF-alpha promoter-driven reporter gene activity. It was proposed that the mechanism of antiviral action of S9a was on the host cell, by blocking TNF-alpha transcription via a Tat-induced tar-independent loop, which decreases downstream NF-kappaB activation of HIV-1 long terminal repeat (LTR). S9a was superior to the first generation compound Canventol, which was superior to the natural compound sarcophytol A, demonstrating that further structure-based enhancement of potency of these compounds is feasible. This study suggests a therapeutic approach against AIDS by application of two drugs, one against a cellular and the other a viral target, which may provide an approach to the problem of frequent emergence of resistant variants to combinations of drugs that target only HIV genes.

Oligodendrocytes utilize a matrix metalloproteinase, MMP-9, to extend processes along an astrocyte extracellular matrix.

Matrix metalloproteinases (MMPs), the key effectors of extracellular matrix remodeling, have been demonstrated to regulate the extension of neurites from neuronal cell bodies. In this report we have addressed the hypothesis that oligodendrocytes (OLs) may utilize a similar mechanism in extending their processes during the initial phase of myelination. Furthermore, given our previous findings linking protein kinase C (PKC) to the OL process outgrowth, we tested the postulate that this signal transduction pathway may regulate MMPs and thus the process outgrowth phenotype. We demonstrate that in response to pharmacologic activators of PKC, cultured human OLs augment their process extension with a concomitant increase in the activity of an MMP, MMP-9, as measured by gelatin zymography. Similarly, the phorbol ester-enhanced process extension and increased MMP-9 activity were both inhibited by calphostin C, a selective PKC inhibitor. Also, MMP inhibitors such as 1,10-phenanthroline and synthetic dipeptides that inactivate the MMP catalytic site negated the 4beta-phorbol-12,13-dibutyrate (PDB)-mediated process extension, further supporting the key role of MMPs in process extension in vitro. Finally, the elevation of MMP-9 protein expression in the mouse corpus callosum, a tissue rich in OL and myelin, coincided with the previously documented temporal increase in myelination that occurs postnatally. Taken together, these data suggest that MMP-9 constitutes an important mediator of OL process outgrowth, and that this protease in turn can be regulated by PKC. The results are relevant not only to the initial steps of myelination during development, but also to the attempted remyelination that has been shown to occur in pathologic conditions such as MS.

The promoting effects of bFGF and astrocyte extracellular matrix on process outgrowth by adult human oligodendrocytes are mediated by protein kinase C.

Process extension by oligodendrocytes (OLs) is a critical early step in myelin formation. We have previously reported that the basal- or phorbol ester-enhanced process outgrowth by adult human OLs is mediated by oligodendroglial protein kinase C (PKC). Recently, we demonstrated that astrocytes facilitated process outgrowth by adult human OLs through the interaction between astrocyte-derived basic fibroblast growth factor (bFGF) and astrocyte extracellular matrix (ECM). If PKC is central to the signal transduction cascade that leads to process formation by OLs, then the effects of bFGF and astrocyte ECM should also involve PKC. In the current study, we have addressed the involvement of PKC in the bFGF- and astrocyte ECM- enhanced process formation by adult human OLs by using a selective inhibitor of PKC, calphostin C. The results show that calphostin C dose-dependently reduced process extension elicited by bFGF and astrocyte ECM, at IC50 concentrations of 24.5 and 26.6 nM, respectively. At the concentrations of calphostin C that inhibited process extension by adult human OLs, necrosis (measured by lactate dehydrogenase release) and apoptosis (determined by using a fluorescent terminal deoxynucleotidyl transferase assay) of OLs did not occur. Finally, we demonstrate that another specific inhibitor of PKC, CGP 41251, also reduced process formation that is elicited by bFGF and astrocyte ECM. Thus, all process-extending agents for adult human OLs identified to date signal through PKC, further implicating PKC of OLs as being central to the production of process extension, an early event in myelinogenesis.

Anti-tumor promoting activity of canventol and its synthetic analogs through inhibition of protein isoprenylation.

Canventol, a synthetic compound, is a new inhibitor of tumor promotion on mouse skin by okadaic acid. We previously reported that canventol acts by inhibiting both protein isoprenylation and tumor necrosis factor-alpha (TNF-alpha) release. In this study we examined the potencies of 10 newly synthesized canventol analogs through their effect on mevalonate metabolism, and then examined 3 representative analogs for inhibition of protein isoprenylation. Since canventol in vitro did not directly inhibit farnesyl protein transferase or geranylgeranyl protein transferase-I, the effects of canventol and its synthetic analogs on the fate of [3H]mevalonate in cells were studied. Canventol at 500 microM changed the ratio of newly synthesized sterols (cholesterol and lathosterol) to ubiquinones from 0.7 to 8.2 in NIH/3T3 cells which had previously been labeled with [3H]mevalonate, suggesting that the altered pattern of mevalonate metabolism is associated with inhibition of protein isoprenylation in the cells. We named this ratio the inhibition of protein isoprenylation index (IPI index). The 10 analogs showed a wide range of IPI indices. Two analogs, S3 and S9 had effects similar to, or stronger than, canventol. Three analogs, C44, C46 and C47, with lower IPI indices, inhibited tumor promotion on mouse skin slightly less than canventol itself did. This study shows that inhibition of protein isoprenylation in the cells, indicated by an increase in the IPI index, is a new biomarker for estimating inhibition of tumor promotion.

Astrocytes promote process outgrowth by adult human oligodendrocytes in vitro through interaction between bFGF and astrocyte extracellular matrix.

Cell-cell interactions regulate many important functions within the central nervous system. In this report, we demonstrate that process outgrowth by adult human oligodendrocytes (OLs) in vitro, an early event of myelinogenesis in vivo, is promoted by astrocytes. To elucidate the mechanisms by which astrocytes might exert this effect, we tested several growth factors known to be produced by astrocytes and found that only basic fibroblast growth factor (bFGF) could enhance process extension by the OL. In correspondence, the treatment of astrocytes with a neutralizing antibody to bFGF decreased their effects in promoting oligodendroglial process outgrowth. The potency of bFGF, however, was only one-third that of astrocytes, and since bFGF did not synergize with other soluble growth factors, we investigated the potential facilitatory role of the extracellular matrix (ECM) deposited by astrocytes. The astrocyte ECM was found to be a promoter of oligodendroglial process extension, and significantly, bFGF synergized with astrocyte ECM to match the potency of live astrocytes. The astrocyte ECM was found in Western blot analyses to contain fibronectin, vitronectin, and laminin. These purified ECM components, as well as heparan sulfate proteoglycan, did not promote oligodendroglial process extension by themselves, although laminin and fibronectin potentiated the effects of bFGF. We conclude that process outgrowth by OLs is guided by astrocytes; the mechanism of the astrocyte effect appears to be due to the combination of bFGF and an unidentified ECM component.

Transneuronal degeneration of thalamic neurons following deafferentation: quantitative studies using [3H]thymidine autoradiography.

Transneuronal degeneration of thalamic neurons following partial deafferentation was studied using [3H]thymidine autoradiography. Timed-pregnant female Sprague-Dawley rats received systemic injections of [3H]thymidine on embryonic day (E) 13, 14 and/or 15. On the day of birth, pups were anesthetized by hypothermia and subjected to unilateral enucleation, unilateral removal of the inferior colliculus or sham lesion. Animals were sacrificed on postnatal day 10 or 30 and the brains processed for autoradiography. Material from sham-lesioned animals demonstrates that neurons destined for the dorsal lateral geniculate nucleus (LGd) undergo final mitoses on E13, 14 and 15. Neurons in the ventral medial geniculate nucleus (MGv) undergo final mitoses on E13 and 14. Thirty days following neonatal unilateral eye removal, the contralateral LGd displays a loss of approximately 30-35% of [3H]thymidine labeled neurons. Neonatal unilateral removal of the inferior colliculus results in a loss of approximately 30-40% of labeled neurons in MGv. For both LGd and MGv, shorter survival times reveal less severe cell loss. Late generated (E15) LGd neurons show less severe loss following enucleation than do earlier generated neurons. These results document the degree of cell loss in sensory thalamic nuclei following deafferentation and demonstrate that [3H]thymidine autoradiography provides a useful quantitative method for assessing anterograde transneuronal cell loss in targeted populations of neurons in the developing central nervous system.