Role of hypoxia-inducible factor-1α in angiogenic–osteogenic coupling

Angiogenesis and osteogenesis are tightly coupled during bone development and regeneration. The vasculature supplies oxygen to developing and regenerating bone and also delivers critical signals to the stroma that stimulate mesenchymal cell specification to promote bone formation. Recent studies suggest that the hypoxia-inducible factors (HIFs) are required for the initiation of the angiogenic–osteogenic cascade. Genetic manipulation of individual components of the HIF/vascular endothelial growth factor (VEGF) pathway in mice has provided clues to how coupling is achieved. In this article, we review the current understanding of the cellular and molecular mechanisms responsible for angiogenic–osteogenic coupling. We also briefly discuss the therapeutic manipulation of HIF and VEGF in skeletal repair. Such discoveries suggest promising approaches for the development of novel therapies to improve bone accretion and repair.     

Seasonality of tuberculosis in India: is it real and what does it tell us?

India has a third of the world's tuberculosis cases. Large-scale expansion of a national programme in 1998 has allowed for population-based analyses of data from tuberculosis registries. We assessed seasonal trends using quarterly reports from districts with stable tuberculosis control programmes (population 115 million). In northern India, tuberculosis diagnoses peaked between April and June, and reached a nadir between October and December, whereas no seasonality was reported in the south. Overall, rates of new smear-positive tuberculosis cases were 57 per 100000 population in peak seasons versus 46 per 100000 in trough seasons. General health-seeking behaviour artifact was ruled out. Seasonality was highest in paediatric cases, suggesting variation in recent transmission.     

Network compensation of cyclic GMP-dependent protein kinase II knockout in the hippocampus by Ca2+-permeable AMPA receptors

Gene knockout (KO) does not always result in phenotypic changes, possibly due to mechanisms of functional compensation. We have studied mice lacking cGMP-dependent kinase II (cGKII), which phosphorylates GluA1, a subunit of AMPA receptors (AMPARs), and promotes hippocampal long-term potentiation (LTP) through AMPAR trafficking. Acute cGKII inhibition significantly reduces LTP, whereas cGKII KO mice show no LTP impairment. Significantly, the closely related kinase, cGKI, does not compensate for cGKII KO. Here, we describe a previously unidentified pathway in the KO hippocampus that provides functional compensation for the LTP impairment observed when cGKII is acutely inhibited. We found that in cultured cGKII KO hippocampal neurons, cGKII-dependent phosphorylation of inositol 1,4,5-trisphosphate receptors was decreased, reducing cytoplasmic Ca²⁺ signals. This led to a reduction of calcineurin activity, thereby stabilizing GluA1 phosphorylation and promoting synaptic expression of Ca²⁺-permeable AMPARs, which in turn induced a previously unidentified form of LTP as a compensatory response in the KO hippocampus. Calcineurin-dependent Ca²⁺-permeable AMPAR expression observed here is also used during activity-dependent homeostatic synaptic plasticity. Thus, a homeostatic mechanism used during activity reduction provides functional compensation for gene KO in the cGKII KO hippocampus.Some gene deletions yield no phenotypic changes because of functional compensation by closely related or duplicate genes (1). However, such duplicate gene activity may not be the main compensatory mechanism in mouse (2), although this possibility is still controversial (3). A second mechanism of compensation is provided by alternative metabolic pathways or regulatory networks (4). Although such compensatory mechanisms have been extensively studied, especially in yeast and nematode (1), the roles of metabolic and network compensatory pathways are not well understood in mouse.Long-term potentiation (LTP) and long-term depression (LTD) are long-lasting forms of synaptic plasticity that are thought to be the cellular basis for learning and memory and proper formation of neural circuits during development (5). NMDA receptor (NMDAR)-mediated synaptic plasticity is a generally agreed postsynaptic mechanism in the hippocampus (5). In particular, synaptic Ca²⁺ influx through NMDARs is critical for LTP and LTD through control of various protein kinases and phosphatases (6). LTP is in part dependent upon the activation of protein kinases, which phosphorylate target proteins (6). Several kinases are activated during the induction of LTP, including cAMP-dependent protein kinase (PKA) and cGMP-dependent protein kinases (cGKs) (6). In contrast, LTD results from activation of phosphatases that dephosphorylate target proteins (6), and calcineurin, a Ca²⁺/calmodulin-dependent protein phosphatase, is important for LTD expression (7). AMPA receptors (AMPARs) are postsynaptic glutamate receptors that mediate rapid excitatory transmission in the central nervous system (8). During LTP, activated kinases phosphorylate AMPARs, leading to synaptic trafficking of the receptors to increase synapse activity (5). For LTD, activation of postsynaptic phosphatases induces internalization of AMPARs from the synaptic membrane, thereby reducing synaptic strength (5). Therefore, both protein kinases and phosphatases control synaptic trafficking of AMPARs, underlying LTP and LTD.AMPARs are tetrameric ligand-gated ion channels that consist of a combinatorial assembly of four subunits (GluA1–4) (9). Studies of GluA1 knockout (KO) mice show that GluA1 is critical for LTP in the CA1 region of the hippocampus (10). GluA1 homomers, like all GluA2-lacking/GluA1-containing receptors, are sensitive to polyamine block and are Ca²⁺-permeable, whereas GluA2-containing AMPARs are Ca²⁺-impermeable (9). Moreover, GluA1 is the major subunit that is trafficked from recycling endosomes to the synaptic membrane in response to neuronal activity (11). Phosphorylation of GluA1 within its intracellular carboxyl-terminal domain (CTD) can regulate AMPAR membrane trafficking (12). Several CTD phosphorylations regulate trafficking (6). In particular, PKA and cGKII both phosphorylate serine 845 of GluA1, increasing the level of extrasynaptic receptors (13, 14). Therefore, activation of PKA and cGKII during LTP induction increases GluA1 phosphorylation, which enhances AMPAR activity at synapses. On the other hand, calcineurin dephosphorylates serine 845 of GluA1, which enables GluA1-containing AMPARs to be endocytosed from the plasma membrane during LTD (15, 16). This removes synaptic AMPARs, leading to reduction of receptor function during LTD. Taken together, the activity-dependent trafficking of synaptic GluA1 is regulated by the status of phosphorylation in the CTD, which provides a critical mechanism underlying LTP and LTD.Several studies have shown that acute inhibition of cGKII impairs hippocampal LTP (13, 17, 18). However, cGKII KO animals show apparently normal LTP in the hippocampus (19), suggesting that a form of functional compensation takes place in the KO hippocampus. Here, we show that cGKII KO reduces Ca²⁺ signals by decreasing cGKII-dependent phosphorylation of inositol 1,4,5-trisphosphate receptors (IP3Rs), which in turn lowers calcineurin activity in hippocampal neurons, which stabilizes phosphorylation of GluA1 in homomeric, Ca²⁺-permeable AMPARs (CPARs). This elevates CPARs at the synapse as a previously unidentified compensatory mechanism for hippocampal LTP in cGKII-deficient animals that is alternative to the form of LTP expressed in WT.     

Punch Incision with Secondary Healing (PISH) Technique for Benign Facial Lesions: An Institutional Experience in 307 Patients

Background  Multiple or solitary facial lesions pose a unique challenge to the attending surgeon in terms of delivering the best cosmetic outcome. There are various methods in dealing with them and the preference of using them is based on the surgeon’s experience, patient expectations, and availability of instruments. One such tool, skin-punch, primarily designed for a biopsy can play a very important therapeutic role in this era of keyhole surgery. In this paper, we assess the technique of punch incision with its combination of secondary healing for various facial lesion. Methods  This observational study, a total of 307 patients with solitary or multiple benign facial lesions were treated with punch incision technique using 2 to 6 mm sterile, disposable skin biopsy punches. Subsequently, the wounds were managed with healing with secondary intention. Results  In our series all superficial wounds epithelized by 7 to 14 days while the deeper lesions epithelized by 14 to 28 days. We had three recurrences which were managed by fusiform excision and one patient had surgical site infection which was managed conservatively. On application of our self-devised facial scar scoring system (SCAR or Scar Cosmesis Assessment and Rating) ³ on all the scars, the mean score was 6 at 1 year followup. Conclusion  Punch incision with healing by secondary intention is a relatively easy, effective, single-stage office procedure. This method can be considered as an alternative method for the removal of various skin lesions, especially on face, thus providing a simple solution to complex problems.     

Systemic Antioxidants and Lung Function in Asthmatics during High Ozone Season: A Closer Look at Albumin,Glutathione, and Associations with Lung Function

Background

Asthma is a chronic airway inflammatory disease with episodic symptoms of wheezing, chest tightness, cough, and shortness of breath. High ambient ozone levels have been associated with increased airway inflammation and asthma morbidity in prior studies. Mechanisms underlying individual susceptibility to asthma exacerbations from poor air quality are not fully understood.

Objective

As part of a panel observational study, we hypothesized that systemic antioxidant ability and antioxidant status may be associated with more stable asthma during high ozone season. Methods: A cross sectional study was performed to evaluate the antioxidant profile in systemic circulation and its associations with clinical parameters in asthmatics and healthy controls during three summers in Atlanta, Georgia.

Results

In this panel of individuals with and without asthma, we found that although systemic glutathione levels were not different between the groups, serum albumin was significantly lower in the asthmatic group. Albumin also significantly correlated with lung function (%FEV1) and asthma quality of life scores. In a subgroup tested, plasma reduced glutathione (GSH) levels were associated with worse airways obstruction.

Conclusion

Antioxidants GSH and albumin may have a role in maintaining lung function and asthma stability during times of poor ambient air quality. Clin Trans Sci 2014; Volume #: 1–5