Foscarnet therapy for ganciclovir-resistant cytomegalovirus retinitis in patients with AIDS.

Infections caused by cytomegalovirus (CMV) resistant in vitro to ganciclovir, defined as requiring greater than 6 mumols of ganciclovir for ED50 have developed in some AIDS patients with progressive CMV retinitis despite chronic ganciclovir therapy. Two such patients (CMV isolates ED50, 9.5-14.5 mumols) were treated with foscarnet, an antiviral pyrophosphate analogue to which both patients' isolates demonstrated in vitro susceptibility (ED50, less than or equal to 300 mumols). Each patient had documented retinitis progression, at 2- and 1- to 5-week intervals, respectively, despite high-dose intravenous ganciclovir therapy. Both patients responded to foscarnet therapy with cessation of viral shedding in urine and blood. After foscarnet therapy was started, retinitis stabilized in the two patients for 12 and 25 weeks, respectively, before progression recurred. Therefore, foscarnet may be effective in immunocompromised patients with rapidly progressive CMV retinitis whose CMV isolates have developed in vitro resistance to ganciclovir.     

Joint Trauma System,Defense Committee on Trauma,and Armed Services Blood Program consensus statement on whole blood

Hemorrhage is the most common mechanism of death in battlefield casualties with potentially survivable injuries. There is evidence that early blood product transfusion saves lives among combat casualties. When compared to component therapy, fresh whole blood transfusion improves outcomes in military settings. Cold-stored whole blood also improves outcomes in trauma patients. Whole blood has the advantage of providing red cells, plasma, and platelets together in a single unit, which simplifies and speeds the process of resuscitation, particularly in austere environments. The Joint Trauma System, the Defense Committee on Trauma, and the Armed Services Blood Program endorse the following: (1) whole blood should be used to treat hemorrhagic shock; (2) low-titer group O whole blood is the resuscitation product of choice for the treatment of hemorrhagic shock for all casualties at all roles of care; (3) whole blood should be available within 30 min of casualty wounding, on all medical evacuation platforms, and at all resuscitation and surgical team locations; (4) when whole blood is not available, component therapy should be available within 30 min of casualty wounding; (5) all prehospital medical providers should be trained and logistically supported to screen donors, collect fresh whole blood from designated donors, transfuse blood products, recognize and treat transfusion reactions, and complete the minimum documentation requirements; (6) all deploying military personnel should undergo walking blood bank prescreen laboratory testing for transfusion transmitted disease immediately prior to deployment. Those who are blood group O should undergo anti-A/anti-B antibody titer testing.     

Metabolic control of the Treg/Th17 axis

The interplay of the immune system with other aspects of physiology is continually being revealed and in some cases studied in considerable mechanistic detail. A prime example is the influence of metabolic cues on immune responses. It is well appreciated that upon activation, T cells take on a metabolic profile profoundly distinct from that of their quiescent and anergic counterparts; however, a number of recent breakthroughs have greatly expanded our knowledge of how aspects of cellular metabolism can shape a T-cell response. Particularly important are findings that certain environmental cues can tilt the delicate balance between inflammation and immune tolerance by skewing T-cell fate decisions toward either the T-helper 17 (Th17) or T-regulatory (Treg) cell lineage. Recognizing the unappreciated immune-modifying potential of metabolic factors and particularly those involved in the generation of these functionally opposing T-cell subsets will likely add new and potent therapies to our repertoire for treating immune mediated pathologies. In this review, we summarize and discuss recent findings linking certain metabolic pathways, enzymes, and by-products to shifts in the balance between Th17 and Treg cell populations. These advances highlight numerous opportunities for immune modulation.     

Granulocyte-Colony Stimulating Factor Reduces Cocaine-Seeking and Downregulates Glutamatergic Synaptic Proteins in Medial Prefrontal Cortex

Psychostimulant use disorder is a major public health issue, and despite the scope of the problem there are currently no Food and Drug Administration (FDA)-approved treatments. There would be tremendous utility in development of a treatment that could help patients both achieve and maintain abstinence. Previous work from our group has identified granulocyte-colony stimulating factor (G-CSF) as a neuroactive cytokine that alters behavioral response to cocaine, increases synaptic dopamine release, and enhances cognitive flexibility. Here, we investigate the role of G-CSF in affecting extinction and reinstatement of cocaine-seeking and perform detailed characterization of its proteomic effects in multiple limbic substructures. Male Sprague Dawley rats were injected with PBS or G-CSF during (1) extinction or (2) abstinence from cocaine self-administration, and drug seeking behavior was measured. Quantitative assessment of changes in the proteomic landscape in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) were performed via data-independent acquisition (DIA) mass spectrometry analysis. Administration of G-CSF during extinction accelerated the rate of extinction, and administration during abstinence attenuated cue-induced cocaine-seeking. Analysis of global protein expression demonstrated that G-CSF regulated proteins primarily in mPFC that are critical to glutamate signaling and synapse maintenance. Taken together, these findings support G-CSF as a viable translational research target with the potential to reduce drug craving or seeking behaviors. Importantly, recombinant G-CSF exists as an FDA-approved medication which may facilitate rapid clinical translation. Additionally, using cutting-edge multiregion discovery proteomics analyses, these studies identify a novel mechanism underlying G-CSF effects on behavioral plasticity.SIGNIFICANCE STATEMENT Pharmacological treatments for psychostimulant use disorder are desperately needed, especially given the disease''s chronic, relapsing nature. However, there are currently no Food and Drug Administration (FDA)-approved pharmacotherapies. Emerging evidence suggests that targeting the immune system may be a viable translational research strategy; preclinical studies have found that the neuroactive cytokine granulocyte-colony stimulating factor (G-CSF) alters cocaine reward and reinforcement and can enhance cognitive flexibility. Given this basis of evidence we studied the effects of G-CSF treatment on extinction and reinstatement of cocaine seeking. We find that administration of G-CSF accelerates extinction and reduces cue-induced drug seeking after cocaine self-administration. In addition, G-CSF leads to downregulation of synaptic glutamatergic proteins in medial prefrontal cortex (mPFC), suggesting that G-CSF influences drug seeking via glutamatergic mechanisms.     

Objectively characterizing Huntington’s disease using a novel upper limb dexterity test

Journal of Neurology - The Clinch Token Transfer Test (C3t) is a bi-manual coin transfer task that incorporates cognitive tasks to add complexity. This study explored the concurrent and convergent...     

Assessing Adolescent Personality Disorders With the Shedler–Westen Assessment Procedure for Adolescents

This two‐part study describes the development and validation of a method for quantifying adolescent personality pathology using the latest edition of the Shedler–Westen Assessment Procedure for Adolescents (SWAP‐II‐A), an instrument designed to be used by clinically experienced observers. In Study 1, experienced psychologists and psychiatrists described a normative clinical sample of 950 North American patients. Study 2 applied the SWAP‐II‐A in a day treatment setting. Results indicated that SWAP‐II‐A personality disorder (PD) scales evidenced high internal consistency, construct validity with Diagnostic and Statistical Manual of Mental Disorders (5th ed.) symptoms and diagnoses, and concurrent validity with Child Behavior Checklist (CBCL) ratings. Independent observers saw patients similarly, and PD assessments were significantly associated with CBCL scale scores and ward behavior.