Emerging role of cyclophilin A in HIV-1 infection: from producer cell to the target cell nucleus.

The HIV-1 genome encodes a small number of proteins with structural, enzymatic, regulatory, and accessory functions. These viral proteins interact with a number of host factors to promote the early and late stages of HIV-1 infection. During the early stages of infection, interactions between the viral proteins and host factors enable HIV-1 to enter the target cell, traverse the cytosol, dock at the nuclear pore, gain access to the nucleus, and integrate into the host genome. Similarly, the viral proteins recruit another set of host factors during the late stages of infection to orchestrate HIV-1 transcription, translation, assembly, and release of progeny virions. Among the host factors implicated in HIV-1 infection, Cyclophilin A (CypA) was identified as the first host factor to be packaged within HIV-1 particles. It is now well established that CypA promotes HIV-1 infection by directly binding to the viral capsid. Mechanistic models to pinpoint CypA's role have spanned from an effect in the producer cell to the early steps of infection in the target cell. In this review, we will describe our understanding of the role(s) of CypA in HIV-1 infection, highlight the current knowledge gaps, and discuss the potential role of this host factor in the post-nuclear entry steps of HIV-1 infection.

AGITG MASTERPLAN: a randomised phase II study of modified FOLFIRINOX alone or in combination with stereotactic body radiotherapy for patients with high-risk and locally advanced pancreatic cancer.

BACKGROUND: Among patients with non-metastatic pancreatic cancer, 80% have high-risk, borderline resectable or locally advanced cancer, with a 5-year overall survival of 12%. MASTERPLAN evaluates the safety and activity of stereotactic body radiotherapy (SBRT) in addition to chemotherapy in these patients. METHODS AND DESIGN: MASTERPLAN is a multi-centre randomised phase II trial of 120 patients with histologically confirmed potentially operable pancreatic cancer (POPC) or inoperable pancreatic cancer (IPC). POPC includes patients with borderline resectable or high-risk tumours; IPC is defined as locally advanced or medically inoperable pancreatic cancer. Randomisation is 2:1 to chemotherapy + SBRT (investigational arm) or chemotherapy alone (control arm) by minimisation and stratified by patient cohort (POPC v IPC), planned induction chemotherapy and institution. Chemotherapy can have been commenced ≤28 days prior to randomisation. Both arms receive 6 × 2 weekly cycles of modified FOLFIRINOX (oxaliplatin (85 mg/m2 IV), irinotecan (150 mg/m2), 5-fluorouracil (2400 mg/m2 CIV), leucovorin (50 mg IV bolus)) plus SBRT in the investigational arm. Gemcitabine+nab-paclitaxel is permitted for patients unsuitable for mFOLFIRINOX. SBRT is 40Gy in five fractions with planning quality assurance to occur in real time. Following initial chemotherapy ± SBRT, resectability will be evaluated. For resected patients, adjuvant chemotherapy is six cycles of mFOLFIRINOX. Where gemcitabine+nab-paclitaxel was used initially, the adjuvant treatment is 12 weeks of gemcitabine and capecitabine or mFOLFIRINOX. Unresectable or medically inoperable patients with stable/responding disease will continue with a further six cycles of mFOLFIRINOX or three cycles of gemcitabine+nab-paclitaxel, whatever was used initially. The primary endpoint is 12-month locoregional control. Secondary endpoints are safety, surgical morbidity and mortality, radiological response rates, progression-free survival, pathological response rates, surgical resection rates, R0 resection rate, quality of life, deterioration-free survival and overall survival. Tertiary/correlative objectives are radiological measures of nutrition and sarcopenia, and serial tissue, blood and microbiome samples to be assessed for associations between clinical endpoints and potential predictive/prognostic biomarkers. Interim analysis will review rates of locoregional recurrence, distant failure and death after 40 patients complete 12 months follow-up. Fifteen Australian and New Zealand sites will recruit over a 4-year period, with minimum follow-up period of 12 months. DISCUSSION: MASTERPLAN evaluates SBRT in both resectable and unresectable patients with pancreatic ductal adenocarcinoma. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry ACTRN12619000409178 , 13/03/2019. Protocol version: 2.0, 19 May 2019.

The Bipolarity Index: a clinician-rated measure of diagnostic confidence.

BACKGROUND: The Bipolarity Index is a clinician-rated scale that rates cardinal features of the disorder across five domains: signs and symptoms, age of onset, course of illness, response to treatment, and family history. We tested the Index in routine clinical practice to identify the optimal cut-off for distinguishing bipolar from non-bipolar disorders. METHOD: Sequential patients in a private practice were rated with the Bipolarity Index (n=1903) at intake. Diagnoses were made with the MINI-6.0.0 International Neuropsychiatric Interview according to DSM-IV-TR criteria, except that cases of antidepressant-induced mania and hypomania were included in the bipolar group. A subset completed the self-rated Mood Disorder Questionnaire (MDQ) (n=1620) or Bipolar Spectrum Diagnostic Scale (BSDS) (n=1179). The primary analysis compared Bipolarity Index scores for bipolar vs. non-bipolar patients using receiver operator curves (ROC) to determine the optimal cut-off score. Secondary outcomes repeated this analysis with the MDQ, MDQ-7 (using only the symptomatic items of the MDQ) and BSDS. RESULTS: At a cut-off of ≥50, the Bipolarity Index had a high sensitivity (0.91) and specificity (0.90). Optimal cut-offs for self-rated scales were: MDQ: ≥7 (sensitivity 0.74, specificity 0.71); MDQ-7: ≥6 (sensitivity 0.77, specificity 0.77); BSDS: ≥12 (sensitivity 0.71, specificity 0.77). LIMITATIONS: The study utilized one rater at a single practice site; the rater was not blinded to the results of the MINI. CONCLUSION: The Bipolarity Index can enhance the clinical assessment of mood disorders and, at a score ≥50 has good sensitivity and specificity for identifying bipolar disorders.

Rechallenge with lamotrigine after a rash: a prospective case series and review of the literature.

OBJECTIVE: To investigate the safety of rechallenge with lamotrigine after an initial rash in patients with refractory bipolar depression. DESIGN: 1) Prospective, open-label case series in a private practice setting. Patients who developed an initial rash on lamotrigine and were refractory to other treatments were offered rechallenge with the drug using very-low-dose titration (5mg every other day or daily for 14 days, then raised every 14 days by daily-dose increments of 5mg; after 25mg/day the titration proceeded according to the manufacturer's guidelines); and 2) A meta-analysis of prior reports of rechallenge with lamotrigine was conducted. MEASURES: A rating scale for rash severity was developed for this study. RESULTS: Of 27 patients rechallenged with lamotrigine, five required discontinuation due to rash or inflammation. Two of these were potentially serious and all resolved with discontinuation of lamotrigine. Review of the literature identified 48 cases of lamotrigine rechallenge with a success rate of 87 percent; in pooled analysis with the current study the success rate was 85 percent. No patients developed Stevens-Johnson syndrome or toxic epidermal necrolysis after rechallenge. The rate of rash was elevated when rechallenge began within four weeks of the initial rash (36% vs. 7%, p=0.002) and reduced when the initial rash had no signs of potential seriousness (0% vs. 23%, p=0.01). CONCLUSIONS: Rechallenge is a viable option after a benign rash on lamotrigine and can be undertaken with more caution after rashes with 1 to 2 signs of potential seriousness. For rashes with three or more signs of seriousness, rechallenge is not well-studied and may carry significant risk. Rechallenge should be avoided within four weeks of the initial rash.

Pramipexole in psychiatry: a systematic review of the literature.

OBJECTIVE: To assess the risks and benefits of pramipexole in psychiatric populations. DATA SOURCES: A PubMed search was performed using the keywords pramipexole and ropinirole, which identified 500 articles. STUDY SELECTION: All clinical studies in psychiatric populations were included in the primary review (24 articles). Studies involving other populations were then reviewed to evaluate potential risks and benefits not identified in the psychiatric studies. DATA EXTRACTION: Effect sizes were calculated from controlled studies. Rates of intolerable side effects and manic switching were estimated by pooled analysis of controlled and uncontrolled studies. DATA SYNTHESIS: Pramipexole has a large effect size (0.6-1.1) in the treatment of both bipolar and unipolar depression with a low short-term rate of manic switching in bipolar patients (1% mania, 5% hypomania). The pooled discontinuation rate for all reasons was 9%. Pramipexole is neuroprotective and exerts beneficial effects on sleep architecture. Pramipexole is associated with 3 rare but serious side effects: sleep attacks, which have only occurred in Parkinson's disease; compulsive behaviors and pathologic gambling, which have occurred in Parkinson's disease and restless legs syndrome; and psychosis, which has occurred in both psychiatric and neurologic populations. CONCLUSIONS: Pramipexole is an important therapeutic option for treatment-resistant bipolar and unipolar depression; further studies are warranted to evaluate its safety in psychiatric patients.