Interleukin 3 enhances cytotoxic T lymphocyte development and class I major histocompatibility complex "re-presentation" of exogenous antigen by tumor-infiltrating antigen-presenting cells.

We show that interleukin 3 (IL-3) enhances the generation of tumor-specific cytotoxic T lymphocytes (CTLs) through the stimulation of host antigen-presenting cells (APCs). The BALB/c (H-2d) spontaneous lung carcinoma line 1 was modified by gene transfection to express ovalbumin as a nominal "tumor antigen" and to secrete IL-3, a cytokine enhancing myeloid development. IL-3-transfected tumor cells are less tumorigenic than the parental cell line, and tumor-infiltrating lymphocytes isolated from these tumors contain increased numbers of tumor-specific CTLs. By using B3Z86/90.14 (B3Z), a unique T-cell hybridoma system restricted to ovalbumin/H-2b and implanting the tumors in (BALB/c x C57BL/6)F1 (H-2d/b) mice, we demonstrate that the IL-3-transfected tumors contain an increased number of a rare population of host cells that can process and "re-present" tumor antigen to CTLs. Electron microscopy allowed direct visualization of these host APCs, and these studies, along with surface marker phenotyping, indicate that these APCs are macrophage-like. The identification of these cells and their enhancement by IL-3 offers a new opportunity for tumor immunotherapy.     

Stimulation of adrenergic activity by desipramine enhances hematopoietic stem and progenitor cell mobilization along with G‐CSF in multiple myeloma: A pilot study

Hematopoietic stem cell (HSC) release is positively regulated by the sympathetic nervous system through the β3 adrenergic receptor. Preclinical studies have demonstrated that the combination of desipramine and G‐CSF resulted in improved HSC mobilization. Here, we present the results of an open‐label single‐arm pilot study in patients with multiple myeloma undergoing autologous stem cell transplantation (ASCT) to assess the safety and efficacy of desipramine combined with G‐SCF to induce HSC mobilization. The primary endpoint was safety of the combination including engraftment kinetics. The secondary endpoint was the proportion of patients who collected ≥5 × 10⁶ CD34⁺ cells/kg. Outcomes were compared with historical matched controls during the same time period with multiple myeloma mobilized with G‐CSF. All study patients received desipramine 100 mg daily for 7 days, starting 4 days prior to G‐CSF administration (D‐3) and continued taking it along with G‐CSF for a total of 7 days. Six of ten patients enrolled completed the protocol with minimal side effects. All of them achieved the target collection of 5 × 10⁶ CD34 cells/kg in a median of 1.5 apheresis session with two patients needing additional plerixafor (16%), while 11 out of 13 patients (85%) achieved the target of 5 × 10⁶ CD34 cells/kg in the historical control group in a median of 2 apheresis procedures and seven patients needed plerixafor (54%). The combination of desipramine and G‐CSF is safe and signals improved mobilization over G‐CSF alone, providing a possible alternative means of mobilization that needs further investigation.     

Isolated hepatic tuberculosis: An uncommon presentation of a common culprit

Hepatic tuberculosis (HTB) is commonly encountered in patients with widespread miliary disease. Isolated affection of the liver is extremely rare. We present a case of a young woman who presented with a subacute afebrile hepatic failure. Investigations including a liver biopsy proved that the presentation was due to granulomatous hepatitis secondary to mycobacterial infection of the liver. It is important that tuberculosis (TB) be kept in mind especially in endemic areas even in atypical clinical scenarios by clinicians, radiologists, and pathologists. Use of anti-tuberculous drugs in such cases is usually successful and must be instituted early.     

Prognostic Value of Computed Tomography Versus Echocardiography Derived Right to Left Ventricular Diameter Ratio in Acute Pulmonary Embolism

BackgroundComputed Tomography (CT) Pulmonary Angiography is the most commonly used diagnostic study for acute pulmonary embolism (PE). Echocardiogram (ECHO) is also used for risk stratification in acute PE, however the diagnostic performance of CT versus ECHO for risk stratification remains unclear.MethodsCT and ECHO right ventricle (RV) and left ventricle (LV) diameters were measured in a retrospective cohort of patients with acute PE. RV:LV diameter ratios were calculated and correlation between CT and ECHO RV:LV ratio was assessed. Sensitivity and specificity for the composite adverse events endpoint of mortality, respiratory failure requiring intubation, cardiac arrest, or shock requiring vasopressors within 30 days of admission were assessed for CT or ECHO derived RV:LV ratio alone and in combination with biomarkers (troponin or B-type natriuretic peptide).ResultsA total of 74 subjects met the inclusion criteria and had a mean age of 62±18 years. The proportion of patients with RV:LV >1 was similar when comparing CT (37.8%) versus ECHO (33.8%) (P = 0.61). A statistically significant correlation was found between CT derived and ECHO derived RV:LV diameter ratio (r = 0.832, P < 0.001). The sensitivity and specificity to predict 30-day composite adverse events for CT versus ECHO derived RV:LV diameter ratio >1 together with positive biomarker status was similar with sensitivity and specificity of 87% and 41% versus 87% and 42%, respectively.ConclusionsIn patients with acute PE, CT and ECHO RV:LV diameter ratio correlate well and identify similar proportion of PE patients at risk for early adverse events. These findings may streamline risk stratification of patients with acute PE.     

Cytomegalovirus IgG Level and Avidity in Breastfeeding Infants of HIV-Infected Mothers in Malawi

Cytomegalovirus (CMV) infection is common among infants of HIV-infected mothers in resource-limited settings. We examined the prevalence and timing of infant CMV infection during the first year of life using IgG antibody and avidity among HIV-exposed infants in Malawi and correlated the results with the presence of detectable CMV DNA in the blood. The Breastfeeding, Antiretrovirals and Nutrition (BAN) study randomized 2,369 mothers and their infants to maternal antiretrovirals, infant nevirapine, or neither for 28 weeks of breastfeeding, followed by weaning. Stored plasma specimens were tested for CMV IgG and antibody avidity from a random subset of infants who had been previously tested with blood CMV PCR and had available specimens at birth and at 24 and 48 weeks of age. Ninety-four of 127 infants (74.0%) tested at 24 weeks of age had CMV IgG of low or intermediate avidity, signifying primary CMV infections. An additional 22 infants (17.3%) had IgG of high avidity; 19 of them had CMV DNA detected in their blood, indicating infant infections. Taken together, these results show that the estimated prevalence of CMV infection at 24 weeks was 88.9%. By 48 weeks of age, 81.3% of infants had anti-CMV IgG; most of them (70.9%) had IgG of high avidity. The CMV serology and avidity testing, combined with the PCR results, confirmed a high rate of primary CMV infection by 6 months of life among breastfeeding infants of HIV-infected mothers. The CMV PCR in blood detected most, but not all, infant CMV infections.     

Stochastic nanoroughness modulates neuron–astrocyte interactions and function via mechanosensing cation channels

Extracellular soluble signals are known to play a critical role in maintaining neuronal function and homeostasis in the CNS. However, the CNS is also composed of extracellular matrix macromolecules and glia support cells, and the contribution of the physical attributes of these components in maintenance and regulation of neuronal function is not well understood. Because these components possess well-defined topography, we theorize a role for topography in neuronal development and we demonstrate that survival and function of hippocampal neurons and differentiation of telencephalic neural stem cells is modulated by nanoroughness. At roughnesses corresponding to that of healthy astrocytes, hippocampal neurons dissociated and survived independent from astrocytes and showed superior functional traits (increased polarity and calcium flux). Furthermore, telencephalic neural stem cells differentiated into neurons even under exogenous signals that favor astrocytic differentiation. The decoupling of neurons from astrocytes seemed to be triggered by changes to astrocyte apical-surface topography in response to nanoroughness. Blocking signaling through mechanosensing cation channels using GsMTx4 negated the ability of neurons to sense the nanoroughness and promoted decoupling of neurons from astrocytes, thus providing direct evidence for the role of nanotopography in neuron–astrocyte interactions. We extrapolate the role of topography to neurodegenerative conditions and show that regions of amyloid plaque buildup in brain tissue of Alzheimer’s patients are accompanied by detrimental changes in tissue roughness. These findings suggest a role for astrocyte and ECM-induced topographical changes in neuronal pathologies and provide new insights for developing therapeutic targets and engineering of neural biomaterials.Cellular homeostasis in the brain tissue is believed to be regulated primarily by a complex spatiotemporal signaling environment involving soluble neurotrophic factors (1, 2). These factors, including neurotrophins such as brain-derived neurotrophic factor, the TGF-β family including bone morphogenetic proteins (BMPs), and the IL-6 superfamily including ciliary neurotrophic factor (CNTF), regulate survival, steer progenitor fate decision, and critically affect the development of the nervous system as well as the homeostasis of the adult CNS (3–6). However, developmental processes such as axon pathfinding, synapse formation, nervous system patterning, neuronal plasticity, and degeneration fail to be explained solely on the basis of soluble factors. There is increasing evidence that physical variables such as the stiffness of a cellular environment influence cell development (7–12). However, the cells of the brain tissue reside in a soft environment that is rich in polysaccharides (13, 14). In the context of neuronal development and neurophysiology, astrocytes have an established role in maintaining neuronal function. They form a vast network that provides the physical and biochemical matrix over which neurons thrive and function (15, 16). The plasticity found in the brain can be attributed in part to the morphological changes that occur in astrocyte processes that can not only alter the geometry of the neuronal environment but also induce dynamic changes in astrocyte–neuron interactions affecting neurotransmission, signal gradients, and the relationship between synapses (15). Interestingly, the changes to the physical aspects of a neuronal environment can originate from changes to morphology of support cells such as astrocytes and also changes to ECM structure and properties. Cells and ECM polysaccharides play an important role in growth, differentiation, and migration of neural precursors, as well as in repair and plasticity in the central nervous system (17, 18). However, in addition to a biological function, cells and macromolecules provide a physically defined environment (19, 20), and we postulate a significant role for topography in neural development. Studies to date have focused on the effects of microscale topography, deterministic roughness, and substrate chemistry on neurite outgrowth and neuronal function (7, 21–23). However, the influence of ECM-like nanotopography on neuronal development and fate is a realm that has not been investigated thus far. Therefore, in this work we specifically focus on the impact of stochastic nanoroughness as would be provided by neighboring cells and ECM molecules on neuronal cell interactions, function, and differentiation.     

Clinical Efficacy of Subgingivally Delivered 1.2% Atorvastatin in Chronic Periodontitis: A Randomized Controlled Clinical Trial

Background: Atorvastatin (ATV) is a specific competitive inhibitor of 3‐hydroxy‐2‐methyl‐glutaryl coenzyme A reductase. Recently, statins have shown pleiotropic effects such as anti‐inflammation and bone stimulation. The aim of the present study is to investigate the effectiveness of 1.2% ATV as an adjunct to scaling and root planing (SRP) in the treatment of intrabony defects (IBDs). Methods: Sixty individuals were randomized into two treatment groups: SRP plus 1.2% ATV and SRP plus placebo gel. At baseline and 3, 6, and 9 months, clinical parameters, which included modified sulcus bleeding index, plaque index, probing depth (PD), and clinical attachment level (CAL), were recorded at baseline. Radiologic assessment of IBD fill was done using computer‐aided software at baseline and 6 and 9 months. Results: Mean PD reduction and mean CAL gain were greater in the ATV group than the placebo group at 3, 6, and 9 months. A significantly greater mean percentage of radiographic bone fill was found in the ATV group (35.49% ± 5.50%) compared to the placebo group (1.82% ± 1.32%) after 9 months. Conclusion: ATV as an adjunct to SRP can provide a new direction in the management of IBDs.     

Locally Delivered 1% Metformin Gel in the Treatment of Smokers with Chronic Periodontitis: A Randomized Controlled Clinical Trial

Background: Metformin (MF) (1,1‐dimethylbiguanide HCl) is one of the most commonly used oral antihyperglycemic agents for the treatment of type 2 diabetes mellitus. Recently, MF has been shown to have bone‐sparing properties. The present study is designed to investigate the effectiveness of MF 1% in an indigenously prepared, biodegradable, controlled‐release gel, as an adjunct to scaling and root planing (SRP) in treatment of vertical defects in smokers with generalized chronic periodontitis (CP). Methods: Fifty patients were categorized into two treatment groups: SRP plus 1% MF and SRP plus placebo. Clinical parameters were recorded at baseline and at 3 and 6 months; they included plaque index (PI), modified sulcus bleeding index (mSBI), probing depth (PD), and clinical attachment level (CAL). At baseline and after 6 months, intrabony defect (IBD) fill was radiologically assessed using computer software. Results: Mean PD reduction and mean CAL gain were found to be greater in the MF group than the placebo group at all visits. Furthermore, a significantly greater mean percentage of bone fill was found in the MF group (26.17% ± 6.66%) than the placebo sites (3.75% ± 8.06%) (P <0.001). Conclusion: There was greater decrease in mSBI and PD and more CAL gain with significant IBD fill at vertical defect sites treated with SRP plus locally delivered MF, versus SRP plus placebo, in smokers with generalized CP.