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Treatment-associated polymorphisms in protease are significantly associated with higher viral load and lower CD4 count in newly diagnosed drug-naive HIV-1 infected patients  [cached]
Theys Kristof,Deforche Koen,Vercauteren Jurgen,Libin Pieter
Retrovirology , 2012, DOI: 10.1186/1742-4690-9-81
Abstract: Background The effect of drug resistance transmission on disease progression in the newly infected patient is not well understood. Major drug resistance mutations severely impair viral fitness in a drug free environment, and therefore are expected to revert quickly. Compensatory mutations, often already polymorphic in wild-type viruses, do not tend to revert after transmission. While compensatory mutations increase fitness during treatment, their presence may also modulate viral fitness and virulence in absence of therapy and major resistance mutations. We previously designed a modeling technique that quantifies genotypic footprints of in vivo treatment selective pressure, including both drug resistance mutations and polymorphic compensatory mutations, through the quantitative description of a fitness landscape from virus genetic sequences. Results Genotypic correlates of viral load and CD4 cell count were evaluated in subtype B sequences from recently diagnosed treatment-naive patients enrolled in the SPREAD programme. The association of surveillance drug resistance mutations, reported compensatory mutations and fitness estimated from drug selective pressure fitness landscapes with baseline viral load and CD4 cell count was evaluated using regression techniques. Protease genotypic variability estimated to increase fitness during treatment was associated with higher viral load and lower CD4 cell counts also in treatment-naive patients, which could primarily be attributed to well-known compensatory mutations at highly polymorphic positions. By contrast, treatment-related mutations in reverse transcriptase could not explain viral load or CD4 cell count variability. Conclusions These results suggest that polymorphic compensatory mutations in protease, reported to be selected during treatment, may improve the replicative capacity of HIV-1 even in absence of drug selective pressure or major resistance mutations. The presence of this polymorphic variation may either reflect a history of drug selective pressure, i.e. transmission from a treated patient, or merely be a result of diversity in wild-type virus. Our findings suggest that transmitted drug resistance has the potential to contribute to faster disease progression in the newly infected host and to shape the HIV-1 epidemic at a population level.
Genetic diversity and drug resistance among newly diagnosed and antiretroviral treatment-naive HIV-infected individuals in western Yunnan: a hot area of viral recombination in China
Chen Min,Ma Yanling,Duan Song,Xing Hui
BMC Infectious Diseases , 2012, DOI: 10.1186/1471-2334-12-382
Abstract: Background The emergence of an HIV-1 epidemic in China was first recognized in Dehong, western Yunnan. Due to its geographic location, Dehong contributed greatly in bridging HIV-1 epidemics in Southeast Asia and China through drug trafficking and injection drug use; and also extensively to the HIV genetic diversity in Yunnan and China. We attempt to monitor HIV-1 in this area by studying the HIV-1 genetic distribution and transmitted drug resistance (TDR) in various at-risk populations. Methods Blood samples from a total of 320 newly HIV-1 diagnosed individuals, who were antiretroviral therapy (ART)-naive, were collected from January 2009 to December 2010 in 2 counties in Dehong. HIV-1 subtypes and pol gene drug resistance (DR) mutations were genotyped. Results Among 299 pol sequences successfully genotyped (93.4%), subtype C accounted for 43.1% (n=129), unique recombinant forms (URFs) for 18.4% (n=55), CRF01_AE for 17.7% (n=54), B for 10.7% (n=32), CRF08_BC for 8.4% (n=25) and CRF07_BC for 1.7% (n=5). Subtype distribution in patients infected by different transmission routes varied. In contract to the previous finding of CRF01_AE predominance in 2002-2006, subtype C predominated in both injecting drug users (IDUs) and heterosexually transmitted populations in this study. Furthermore, we found a high level of BC, CRF01_AE/C and CRF01_AE/B/C recombinants suggesting the presence of active viral recombination in the area. TDR associated mutations were identified in 4.3% (n=13) individuals. A total of 1.3% of DR were related to protease inhibitors (PIs), including I85IV, M46I and L90M; 0.3% to nucleoside reverse transcriptase inhibitors (NRTIs), including M184I; and 2.7% to non-nucleoside reverse transcriptase inhibitors (NNRTIs), including K103N/S, Y181C, K101E and G190A. Conclusion Our work revealed diverse HIV-1 subtype distributions and intersubtype recombinations. We also identified a low but significant TDR mutation rate among ART-naive patients. These findings enhance our understanding of HIV-1 evolution and are valuable for the development and implementation of a comprehensive public health approach to HIV-1 DR prevention and treatment in the region.
Reduced Central Memory CD4+ T Cells and Increased T-Cell Activation Characterise Treatment-Naive Patients Newly Diagnosed at Late Stage of HIV Infection  [PDF]
Francesca Bai,Camilla Tincati,Esther Merlini,Carlotta Pacioni,Elisabetta Sinigaglia,Giovanni Carpani,Antonella d'Arminio Monforte,Giulia Marchetti
AIDS Research and Treatment , 2012, DOI: 10.1155/2012/314849
Abstract: Objectives. We investigated immune phenotypes of HIV+ patients who present late, considering late presenters (LPs, CD4+ < 350/μL and/or AIDS), advanced HIV disease (AHD, CD4+ < 200/μL and/or AIDS), and AIDS presenters (AIDS-defining condition at presentation, independently from CD4+). Methods. Patients newly diagnosed with HIV at our clinic between 2007–2011 were enrolled. Mann-Whitney/Chi-squared tests and logistic regression were used for statistics. Results. 275 patients were newly diagnosed with HIV between January/2007–March/2011. 130 (47%) were LPs, 79 (29%) showed AHD, and 49 (18%) were AIDS presenters. LP, AHD, and AIDS presenters were older and more frequently heterosexuals. Higher CD8+%, lower CD127+CD4+%, higher CD95+CD8+%, CD38+CD8+%, and CD45R0+CD38+CD8+% characterized LP/AHD/AIDS presentation. In multivariate analysis, older age, heterosexuality, higher CD8+%, and lower CD127+CD4+% were confirmed associated with LP/AHD. Lower CD4+ and higher CD38+CD8+% resulted independently associated with AIDS presentation. Conclusions. CD127 downregulation and immune activation characterize HIV+ patients presenting late and would be studied as additional markers of late presentation. 1. Introduction Despite reduced morbidity and mortality achieved by highly active antiretroviral therapy (HAART) and extensive work encouraging earlier HIV testing, late presentation of HIV remains a relevant clinical problem. Up to 15%–38% of HIV positive patients present late for testing with a low CD4+ T-cell count, high viral load, and severe alterations of their immune system [1]. Focusing on the Italian scenario, 39% of new HIV diagnosis occur late [2]. Compared to patients diagnosed with HIV early in the course of infection, late presenters are at higher probability of clinical progression and treatment-related adverse events and introduce HAART later than recommended by current antiretroviral therapy guidelines [3, 4]. Furthermore, late presentation deeply impacts on healthcare system and community in terms of resource use and higher risk of HIV transmission to sexual partners [5]. Recently, two different classifications of late presentation have been established by the European AIDS Clinical Society [6]: all patients who present with a CD4+ T-cell count less than 350?cells/ L and/or an AIDS-defining condition at, or within a month after, HIV diagnosis are identified as “late presenters.” This definition allows for the identification of patients that should be considered for treatment in accordance with current guidelines. Secondly, focusing on the established risk
POEMS Syndrome Diagnosed 10?Years after Disabling Peripheral Neuropathy
Viet H. Nguyen
Case Reports in Medicine , 2011, DOI: 10.1155/2011/126209
Abstract: Peripheral neuropathy is characterized as a generalized, relatively homogeneous process affecting many peripheral nerves and predominantly affecting distal nerves. The epidemiology of peripheral neuropathy is limited since the disease presents with varying etiology, pathology, and severity. Toxic, inflammatory, hereditary, and infectious factors can cause damage to the peripheral nerves resulting in peripheral neuropathy. Peripheral neuropathy is most commonly caused by diabetes, alcohol, HIV infection, and malignancy. We report a case of a 42-year-old female with 10-year history of progressively worsening peripheral neuropathy, hypothyroidism, and skin changes who presents with dyspnea secondary to recurrent pleural and pericardial effusions. Prior to her arrival, her peripheral neuropathy was believed to be secondary to chronic demyelinating inflammatory polyneuropathy (CDIP) given elevated protein in the cerebral spinal fluid (CSF) which was treated with intravenous immunoglobulin (IVIG) and corticosteroids. Unfortunately, her peripheral neuropathy did not have any improvement. Incidentally, patient was found to have splenomegaly and papilledema on physical exam. Serum protein electrophoresis showed a monoclonal pattern of IgA lambda. Patient met the diagnostic criteria for POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome. An underlying diagnosis of POEMS syndrome should be considered in patients with chronic debilitating neuropathy and an elevated protein in the CSF.
The Choice of Regimens Based on Bortezomib for Patients with Newly Diagnosed Multiple Myeloma  [PDF]
Jingsong He, Li Yang, Xiaoyan Han, Gaofeng Zheng, Weiyan Zheng, Guoqing Wei, Wenjun Wu, Xiujin Ye, Jimin Shi, Wanzhuo Xie, Li Li, Jie Zhang, Weijia Huang, Yi Zhao, He Huang, Xuejin Zhang, Jiaping Fu, Zhen Cai
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0099174
Abstract: Introduction Bortezomib has significantly improved multiple myeloma (MM) response rates, but strategies for choosing bortezomib-based regimens for initial MM therapy are not standardized. Here, we describe four bortezomib-based therapies in Chinese MM patients to determine the optimal chemotherapeutic approach. Methods Newly diagnosed symptomatic MM patients at three hematological centers between February 1, 2006 and May 31, 2013 were treated with therapies including bortezomib plus dexamethasone (PD) or combinations of PD with either adriamycin (PAD), cyclophosphamide (PCD) or thalidomide (PTD) for every 28 days. Results The overall response rate of all the 215 eligible patients was 90.2%. The ORR for PCD, PAD, PTD and PD were 97.4%, 93.2%, 85.3% and 77.8% while the effects with VGPR or better were 63.7%, 62.7%, 44.2% and 37.8%, respectively. The effect of ORR, VGPR and CR/nCR for the PCD regimen was better than the PD protocol. Median PFS for all patients was 29.0 months with significant differences observed among treatment groups. Median OS of all the patients was not reached, but three-drug combinations were superior to PD alone. Frequently observed toxicities were neutropenia, thrombocytopenia, fatigue, infection, herpes zoster, and peripheral neuropathy. The incidence of peripheral neuropathy (PN) in PTD group was significantly higher than other three groups, especially grade 2–3 PN. Treatment with anti-viral agent acyclovir significantly reduced the incidence of herpes zoster. Conclusions Our experience indicated that bortezomib-based regimens were effective and well-tolerated in the Chinese population studied; three-drug combinations PCD, PAD were superior to PD, especially with respect to PCD.
Tipifarnib in the treatment of newly diagnosed acute myelogenous leukemia  [cached]
Judith E Karp,Jeffrey E Lancet
Biologics: Targets and Therapy , 2008,
Abstract: Judith E Karp1, Jeffrey E Lancet21Division of Hematologic Malignancies, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA; 2H. Lee Moffitt Comprehensive Cancer Center, Tampa, Florida, USAAbstract: Farnesyltransferase inhibitors (FTIs) represent a new class of signal transduction inhibitors that block the processing of cellular polypeptides that have cysteine terminal residues and, by so doing, interdict multiple pathways involved in proliferation and survival of diverse malignant cell types. Tipifarnib is an orally bioavailable, nonpeptidomimetic methylquinolone FTI that has exhibited clinical activity in patients with myeloid malignancies including elderly adults with acute myelogenous leukemia (AML) who are not candidates for traditional cytotoxic chemotherapy, patients with high-risk myelodysplasia, myeloproliferative disorders, and imatinib-resistant chronic myelogenous leukemia. Because of its relatively low toxicity profile, tipifarnib provides an important alternative to traditional cytotoxic approaches for elderly patients who are not likely to tolerate or even benefit from aggressive chemotherapy. In this review, we will focus on the clinical development of tipifarnib for treatment of newly diagnosed AML, both as induction therapy for elderly adults with poor-risk AML and as maintenance therapy following achievement of first complete remission following induction and consolidation therapies for poor-risk AML. As with all other malignancies, the optimal approach is likely to lie in rational combinations of tipifarnib with cytotoxic, biologic and/or immunomodulatory agents with non-cross-resistant mechanisms of action. Gene expression profi ling has identified networks of differentially expressed genes and gene combinations capable of predicting response to single agent tipifarnib. The clinical and correlative laboratory trials in progress and under development will provide the critical foundations for defining the optimal roles of tipifarnib and in patients with AMl and other hematologic malignancies.Keywords: farnesylation, farnesyltransferase inhibitor, acute myelogenous leukemia (AML), signal transduction, gene expression, tipifarnib
Belatedly diagnosed acute motor axonal neuropathy after cardiac surgery  [PDF]
Chong Tae Kim, Todd Beery
Case Reports in Clinical Medicine (CRCM) , 2013, DOI: 10.4236/crcm.2013.27105
Abstract: Surgery has been reported a rare cause of Guillain-Barré syndrome (GBS), but a recent retrospective study reported a much higher incidence rate for post-surgical patients. There are several case reports of GBS presenting after cardiac surgical procedures. All these cases were diagnosed as acute inflammatory demyelinating polyradiculoneuropathy (AIDP). We described a case of acute motor axonal neuropathy (AMAN) after cardiac surgery. Clinical features were reviewed along with spinal magnetic resonance imaging (MRI) and cerebral spinal fluid (CSF) analysis. Sequential electrodiagnostic studies (EDx) were performed. This case represented a rare complication of AMAN with urinary retention after cardiac surgery.

Induction Therapy and Stem Cell Mobilization in Patients with Newly Diagnosed Multiple Myeloma  [PDF]
Roberto Ria,Antonia Reale,Antonio Giovanni Solimando,Giuseppe Mangialardi,Michele Moschetta,Lucia Gelao,Giuseppe Iodice,Angelo Vacca
Stem Cells International , 2012, DOI: 10.1155/2012/607260
Abstract: Autologous stem cell transplantation (ASCT) is considered the standard therapy for younger patients with newly diagnosed symptomatic multiple myeloma (MM). The introduction into clinical practice of novel agents, such as the proteasome inhibitor bortezomib and the immunomodulatory derivatives (IMiDs) thalidomide and lenalidomide, has significantly contributed to major advances in MM therapy and prognosis. These novel agents are incorporated into induction regimens to enhance the depth of response before ASCT and further improve post-ASCT outcomes. Between January 2000 and November 2011, 65 patients with MM were transplanted in the Department of Biomedical Science and Clinical Oncology at the University of Bari. According to Durie-Salmon, 60 patients had stage III of disease and 5 stage II. Only 7 patients were in stage B (renal failure). Induction regimens that were administered in two or more cycles were VAD (vincristine, adriamycin, and dexamethasone), Thal-Dex (thalidomide, dexamethasone), Len-Dex (lenalidomide, dexamethasone), Vel-Dex (bortezomib, dexamethasone), VTD (bortezomib, thalidomide, and dexamethasone), and PAD (bortezomib, pegylated liposomal doxorubicin, and dexamethasone). In mobilization procedure, the patients received cyclophosphamide and granulocyte colony-stimulating factor (G-CSF). The number of cells collected through two or more leukapheresess, response after induction, and toxicity were evaluated to define the more adequate up-front induction regimen in transplantation-eligible MM patients. 1. Introduction Over the last decade, high-dose chemotherapy followed by ASCT has been considered the standard of care for younger patients with newly diagnosed MM, based on the increased rate of complete response (CR), prolonged overall survival (OS), and reduced side effects compared with conventional chemotherapy in several randomized studies [1–4]. Patients who are eligible for early ASCT typically receive a limited number of cycles of induction therapy to reduce tumor cell mass and bone marrow plasma cell infiltration before collection of peripheral blood stem cells [5]. Compared with conventional treatments used in the past, a number of novel agents are now available which affect increased rates of CR [6–8]. The reach of CR after both induction therapy and ASCT is one of the strongest predictors of long-term outcomes and represents a major endpoint of the treatment strategy in younger patients together with maintenance of a durable CR [5]. The initial rationale for the use of IMiDs in MM was their known antiangiogenic activity,
Generalized Chorea-Ballism Case with Newly Diagnosed Diabetes Mellitus
Betül ?ZD?LEK,Esma KOBAK,Mustafa üLKER,Gülay KENANG?L
Marmara Medical Journal , 2012,
Abstract: Chorea and ballism are hyperkinetic movement disorders. Hyperglycemia is a rare cause of these movement disorders. Here, we report a case of generalized chorea-ballism with newly diagnosed diabetes mellitus. (Marmara Medical Journal 2012;25:156-8)
Thyroid Dysfunction in Newly Diagnosed Type 1 Diabetic Children
Seyed Mehdi Monajemzadeh,Nooshin Najafian
Research Journal of Biological Sciences , 2012,
Abstract: Thyroid disease may affect diabetes management. The aim of this study, was to investigate the prevalence of thyroid dysfunction among children and adolescents with newly diagnosed type I diabetes in Iran. A case-control study was done between March 2005 to August 2008 in the pediatric ward of a tertiary Hospital, Ahwaz, Iran. In words 75 consecutive newly diagnosed type 1 subjects were selected and were compared with 105 healthy control children. Physical examination for signs of thyroid dysfunction and estimation of thyroid size by using palpation were performed and TSH and T3 and T4 were measured to evaluate prevalence of thyroid dysfunction. Prevalence of thyroid dysfunction in diabetics was 14.6%; of them 9.3% were subclinical hypothyroidism, 4% hypothyroidism and 1.3% subclinical hyperthyroidism, which were higher than normal controls. Goiter prevalence by palpation was the same in both groups. Because of higher prevalence of thyroid dysfunction in newly diagnosed type 1 diabetes than in controls, we confirm the recommendation that thyroid testing be done at diagnosis and routinely in children and adolescents with type I diabetes.
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