Geriatric Assessment and Frailty Scores Predict Mortality in Myeloma: Systematic Review and Meta-analysis

The incidence of multiple myeloma is increasing as the proportion of older adults is growing rapidly. A critical evaluation of the evidence available is needed to guide the management of older patients with myeloma. A systematic review was conducted to report the prognostic value of geriatric assessment and frailty scores in older patients with multiple myeloma. We conducted a literature search in February and August 2018. Two researchers extracted the data and assessed the quality of the studies. Geriatric assessment and frailty scores were defined as those evaluating at least 2 geriatric domains. Main outcomes were mortality or toxicity. We estimated the pooled hazard ratios (HR) with 95% confidence intervals (CIs) using a random-effects model. We screened titles and abstracts of 1672 citations for eligibility. Seven studies were included in the qualitative analysis, of which 3 were included in the meta-analysis. Two studies reported similar risks of hematologic adverse events in intermediate-fit and in frail patients compared to frail, but a significantly increased risk of nonhematologic adverse events in frail patients compared to fit patients. In meta-analysis, a significantly increased HR for death was observed in patients with activity of daily living score ≤ 4 (pooled HR = 1.576; 95% CI, 1.051-2.102; χ² = 0.87; P = .647; I² = 0). Patients classified as frail showed higher risk of death than fit patients (pooled HR = 2.169; 95% CI, 1.002-2.336; χ² = 3.02; P = .221; I² = 33.7%). GA and frailty score are effective in predicting mortality in older adults with myeloma.     

Mechanism of accelerated current decay caused by an episodic ataxia type-1-associated mutant in a potassium channel pore

In Kv1.1, single point mutants found below the channel activation gate at residue V408 are associated with human episodic ataxia type-1, and impair channel function by accelerating decay of outward current during periods of membrane depolarization and channel opening. This decay is usually attributed to C-type inactivation, but here we provide evidence that this is not the case. Using voltage-clamp fluorimetry in Xenopus oocytes, and single-channel patch clamp in mouse ltk- cells, of the homologous Shaker channel (with the equivalent mutation V478A), we have determined that the mutation may cause current decay through a local effect at the activation gate, by destabilizing channel opening. We demonstrate that the effect of the mutant is similar to that of trapped 4-aminopyridine in antagonizing channel opening, as the mutation and 10 mm 4-AP had similar, nonadditive effects on fluorescence recorded from the voltage-sensitive S4 helix. We propose a model where the Kv1.1 activation gate fails to enter a stabilized open conformation, from which the channel would normally C-type inactivate. Instead, the lower pore lining helix is able to enter an activated-not-open conformation during depolarization. These results provide an understanding of the molecular etiology underlying episodic ataxia type-1 due to V408A, as well as biophysical insights into the links between the potassium channel activation gate, the voltage sensor and the selectivity filter.     

Anti-colitis and -adhesion effects of daikenchuto via endogenous adrenomedullin enhancement in Crohn's disease mouse model

Background and aimsAdrenomedullin (ADM) is a member of the calcitonin family of regulatory peptides, and is reported to have anti-inflammatory effects in animal models of Crohn's disease (CD). We investigated the therapeutic effects of daikenchuto (DKT), an extracted Japanese herbal medicine, on the regulation of endogenous ADM in the gastrointestinal tract in a CD mouse model.MethodsColitis was induced in mice by intrarectal instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS); afterwards, DKT was given orally. Colonic damage was assessed on day 3 by macroscopic and microscopic observation, enzyme immunoassays of proinflammatory cytokines in the colonic mucosa, and serum amyloid A (SAA), a hepatic acute-phase protein. To determine the involvement of ADM, an ADM antagonist was instilled intrarectally before DKT administration. The effect of DKT on ADM production by intestinal epithelial cells was evaluated by enzyme immunoassay and real-time PCR.ResultsDKT significantly attenuated mucosal damage and colonic inflammatory adhesions, and inhibited elevations of SAA in plasma and the proinflammatory cytokines TNFα and IFNγ in the colon. Small and large intestinal epithelial cells produced higher levels of ADM after DKT stimulation. A DKT-treated IEC-6 cell line also showed enhanced ADM production at protein and mRNA levels. Abolition of this effect by pretreatment with an ADM antagonist shows that DKT appears to exert its anti-colitis effect via up-regulation of endogenous ADM in the intestinal tract.ConclusionDKT exerts beneficial effects in a CD mouse model through endogenous release and production of ADM. Endogenous ADM may be a therapeutic target for CD.     

Multiple Antigen Peptide Vaccines against Plasmodium falciparum Malaria

The multiple antigen peptide (MAP) approach is an effective method to chemically synthesize and deliver multiple T-cell and B-cell epitopes as the constituents of a single immunogen. Here we report on the design, chemical synthesis, and immunogenicity of three Plasmodium falciparum MAP vaccines that incorporated antigenic epitopes from the sporozoite, liver, and blood stages of the life cycle. Antibody and cellular responses were determined in three inbred (C57BL/6, BALB/c, and A/J) strains, one congenic (HLA-A2 on the C57BL/6 background) strain, and one outbred strain (CD1) of mice. All three MAPs were immunogenic and induced both antibody and cellular responses, albeit in a somewhat genetically restricted manner. Antibodies against MAP-1, MAP-2, and MAP-3 had an antiparasite effect that was also dependent on the mouse major histocompatibility complex background. Anti-MAP-1 (CSP-based) antibodies blocked the invasion of HepG2 liver cells by P. falciparum sporozoites (highest, 95.16% in HLA-A2 C57BL/6; lowest, 11.21% in BALB/c). Furthermore, antibodies generated following immunizations with the MAP-2 (PfCSP, PfLSA-1, PfMSP-1₄₂, and PfMSP-3b) and MAP-3 (PfRAP-1, PfRAP-2, PfSERA, and PfMSP-1₄₂) vaccines were able to reduce the growth of blood stage parasites in erythrocyte cultures to various degrees. Thus, MAP-based vaccines remain a viable option to induce effective antibody and cellular responses. These results warrant further development and preclinical and clinical testing of the next generation of candidate MAP vaccines that are based on the conserved protective epitopes from Plasmodium antigens that are widely recognized by populations of divergent HLA types from around the world.Vaccinations against several deadly infectious agents continue to save millions of lives annually and have improved the quality of life of tens of millions of individuals by significantly preventing or reducing the transmission of several pandemic and locally transmitted infectious diseases. Thus, there are reasons to believe that a successful malaria vaccine would not only significantly reduce malaria mortality and morbidity but also become an important tool in disease control efforts.The quest to develop a malaria vaccine began more than 6 decades ago with successful vaccination against malaria in birds (16). Since then, several decades of research in experimental models have demonstrated that both whole-parasite- and subunit (recombinant and synthetically produced)-based vaccines can induce protective immunity when delivered under optimal conditions. However, after hundreds of millions of dollars in investments and several dozen clinical trials, recombinant-protein-based candidate malaria vaccines have failed to induce the level of protection that would warrant production as licensed vaccines. The most successful recombinant vaccine, RTS,S, has undergone trials and, at its best, induced 53% protection against clinical malaria in a placebo-controlled clinical trial that involved 5- to 17-month-old children in Kenya and Tanzania (3). The limited success of recombinant vaccines has led to a surge in interest to produce and test whole attenuated parasite-based vaccines against malaria, most of which are based on live attenuated Plasmodium falciparum sporozoites (24, 59). Nonetheless, the whole-parasite-based vaccination approach presents unique challenges in terms of safety, residual virulence, and the potential for reversion in virulence, mode of delivery, and difficulties associated with sufficient production for en masse vaccination. Thus, given the limited amount of clinical immunity conferred by the recombinant-protein-based vaccines and the perceived hurdles with the whole-parasite-based vaccines, it is imperative that malaria researchers continue to apply alternative options to develop and test candidate malaria vaccines.The complex multistage life cycle of malaria parasites presents unique challenges for vaccine development. Immunity against malaria parasites is stage dependent and species dependent. Many malaria researchers believe that a single-antigen vaccine representing only one stage of the life cycle will not be sufficient and that a multiantigen, multistage vaccine that targets different stages of parasite development is necessary to induce effective immunity. Based on these assumptions, it is reasonable to argue that separate malaria vaccines may be needed to target the different parasite developmental stages and also multiple Plasmodium species that may be prevalent in a given area. In this context, a synthetic-peptide-based approach where multiple protective epitopes representing different stages of the life cycle, possibly from more than one Plasmodium species, are assembled in a vaccine construct appears to be an attractive approach for malaria vaccine development.The first peptide-based malaria vaccine was based on the repeat sequences of P. falciparum that underwent clinical testing in 1987 (21). Since then, a number of synthetic peptide vaccines have been produced for both murine (P. berghei and P. yoelii) and human (P. falciparum and P. vivax) malarias and tested for immunogenicity (1, 31, 39, 61) or immunogenicity and efficacy (32, 52, 56). However, in spite of the early momentum, several theoretical considerations and technological hurdles have slowed the progress of this vaccine development approach. Some of the perceived major arguments against the peptide-based vaccine approach include their short linear nature that prohibited the inclusion of multiple protective B-cell and T-cell epitopes in the same construct and the presumed inability to create the Cys-Cys disulfide bonds in conformation-dependent epitopes. However, recent studies suggest that protein domains that mimic the native protein structure can be created in chemically synthesized peptide constructs that include conformationally correct Cys-Cys bonds to create immunologically active molecules (7, 48, 49). In addition, recently it has been suggested that large-scale and cost-effective synthesis of peptide-based vaccines is possible (8).Currently, a reasonably large database of unique B-cell and T-cell epitopes from Plasmodium proteins, including those from human P. falciparum and P. vivax malarias, has become available. By conducting a comprehensive meta-analysis of available data for Plasmodium immune epitopes, Vaughan et al. have identified more than 5,000 unique B-cell and T-cell epitopes for malaria parasites (60). Several of the P. falciparum and P. vivax epitopes were identified in extensive field studies conducted over the last 2 decades (12, 23, 35, 57) and by computer-based predictions of immune epitopes by analysis of genomic and proteomic databases; some of these predictions were validated in HLA-peptide binding studies and in vitro immunological studies (4, 11-13, 29). In this communication, we report the design, synthesis, and immunogenicity studies of three multiple antigen peptide (MAP)-based vaccines for P. falciparum malaria. These MAP vaccines were based on immunodominant B-cell and T-cell epitopes from the major malaria vaccine candidates, circumsporozoite protein (CSP), liver stage antigen 1 (LSA-1), merozoite surface protein 1 (MSP-1) and MSP-3, serine repeat antigen (SERA), and rhoptry-associated protein 1 (RAP-1) and RAP-2, representing the sporozoite, liver, and asexual blood stages of P. falciparum parasites. The synthesis of MAP vaccines was based on a novel technology developed by our group (6, 27). We are presenting data demonstrating the immunogenicity of these P. falciparum MAP vaccines in three inbred mouse strains (C57BL/6, BALB/c, and A/J), one congenic mouse strain (C57BL/6 strain expressing the HLA-A2 molecule), and one outbred mouse strain (CD1). The HLA-A2 transgenic mice were included in these studies to facilitate the determination of the immunogenicity of a CSP-based peptide in MAP-1 that was recognized by supertypes HLA-A*0202 and HLA-A*6802 (12).     

Induction of immunogenicity by live attenuated Leishmania donovani centrin deleted parasites in dogs

Zoonotic visceral leishmaniasis, caused by the intracellular protozoan parasite Leishmania infantum, is a neglected tropical disease that is often fatal when untreated. Dogs are considered the main reservoir of L. infantum in zoonotic VL as the presence of infected dogs may increase the risk for human infection. Canine visceral leishmaniasis (CVL) is a major veterinary and public health problem in Southern Europe, Middle East and South America. Control of animal reservoirs relies on elimination of seropositive dogs in endemic areas. However, treatment of infected dogs is not considered a favorable approach as this can lead to emergence of drug resistance since the same drugs are used to treat human infections. Therefore, vaccination against CVL remains the best alternative in control of the animal reservoirs. In this study, we present data on the immunogenicity profile of a live attenuated parasite LdCen^−/− in a canine infection model and compared it to that of Leishmune^®, a commercially available recombinant vaccine. The immunogenicity of the LdCen^−/− parasites was evaluated by antibody secretion, production of intracytoplasmic and secreted cytokines, activation and proliferation of T cells. Vaccination with LdCen^−/− resulted in high immunogenicity as revealed by the higher IgGTotal, IgG1, and IgG2 production and higher lymphoproliferative response. Further, LdCen^−/− vaccinated dogs showed higher frequencies of activated CD4+ and CD8+ T cells, IFN-γ production by CD8+ T cells, increased secretion of TNF-α and IL-12/IL-23p40 and decreased secretion of IL-4. These results contribute to the understanding of immunogenicity elicited by live attenuated L. donovani parasites and, consequently, to the development of effective vaccines against visceral leishmaniasis.     

Clinical Manifestations of Secondary Syphilis

The results of a prospective study, aimed at having a fresh look at the clinical features of secondary syphilis in 89 patients, are presented. Eighty-one (91.0%) had syphilides, and of these, 24 (29.6%) had atypical morphology. Two or more groups of lymph nodes were enlarged in 60, and hepatosplenomegaly was seen in 20 (22.5%) patients. Condylomata data in atypical sites occurred in six patients. A total of 10 patients had alopecia on the scalp, and anterior uveitis was seen in 7 (7.9%). The clear CSF showed minimal elevation of lymphocytes in one of the 21 patients on whom lumbar puncture was performed and may, therefore, be considered unnecessary as a routine procedure. An awareness of the varied clinical presentations would assist in early diagnosis of the disease and help reduce its complications.     

Schistosomal genital granulomas: a report of 10 cases.

Genital lesions caused by Schistosoma spp are difficult to diagnose because of their similarity to those of common sexually transmitted diseases (STD). Over two years 10 cases of genital lesions were identified by skin or cervical biopsies as being caused by schistosomal infection. Definitive diagnosis is possible only when schistosomal ova are identified by histological examination of biopsy specimens. Routine biopsies of proliferative genital lesions are therefore recommended in regions where Schistosoma spp are endemic.     

Polymorphisms in various coagulation genes in black South African women with placental abruption

This pilot study examined Factor V Leiden (R506Q), prothrombin (20210G → A), thrombomodulin (A455V) and MTHFR (677C → T ) in 100 Zulu-speaking black South African women with placental abruption and 217 controls. The Factor V Leiden and prothrombin variant gene alleles were not detected in either patient or control groups. The thrombomodulin polymorphic variant was not seen in the patient group but three heterozygotes (1%) were found in the controls. No homozygotes for the MTHFR T677 variant were detected in the patients but two (1%) were noted in the controls; the normal and heterozygote genotype and allele frequencies for this polymorphism were similar in the two groups.     

Silent sinus syndrome.

BACKGROUND: Silent sinus syndrome (SSS) is similar to and a subset of chronic maxillary atelectasis (CMA), which refers to a persistent decrease in sinus maxillary volume due to inward retraction of the maxillary sinus walls secondary to obstruction of the osteomeatal complex. It differs from CMA, however, in that there is no pain or maxillary sinus congestion. Patients with SSS usually manifest spontaneous unilateral enophthalmos and hypoglobus, with no history of facial trauma or surgery. They also do not have any nasal symptoms, sinusitis, or pain. CASE REPORT: A 28-year-old woman with asymptomatic enophthalmos and hypoglobus is described. The presentaton, diagnosis, and treatment of silent sinus syndrome are discussed. CONCLUSIONS: Silent sinus syndrome should be included in the differential diagnosis of enophthalmos and hypoglobus in the absence of trauma, surgery, and nasal symptoms. In addition to a thorough eye examination, axial and coronal computerized tomography of the sinus and orbits should be obtained to confirm the diagnosis.     

Diagnosis of imported malaria by Plasmodium lactate dehydrogenase (pLDH) and histidine-rich protein 2 (PfHRP-2)-based immunocapture assays.

This study was conducted to evaluate the performance of two rapid non-microscopic assays: Plasmodium lactate dehydrogenase (pLDH) assay (OptiMAL) and Plasmodium falciparum histidine-rich protein 2 (PfHRP-2) assay (ICT Malaria). The assays were used to detect malaria infection in 515 immigrants living in Kuwait. The performance of both assays was compared to that of microscopy of Giemsa-stained thick blood films and to each other. Of the 515 patients tested, 163 were positive for malaria parasites by microscopy of thick blood film. Of these, 87 were infected with Plasmodium vivax parasites, 63 with P. falciparum, 1 with Plasmodium malariae, and 12 had mixed infections of P. falciparum and P. vivax. The PfHRP-2 assay detected 53 P. falciparum infections and, as expected, failed to detect all but one case of P. vivax. Three cases of mixed infections were also not detected by this assay. The pLDH assay detected 56 P. falciparum cases and 77 P. vivax infections but failed to detect 4 cases of mixed infections. Compared to microscopy, the performance of both the assays to diagnose P. falciparum infection was comparable. The sensitivity for the PfHRP-2 assay was 82% with a specificity of 99.0% and for the pLDH assay the sensitivity was 89% with a specificity of 99.5%. The PfHRP-2 assay detected 4 false positive cases, 2 of which were also detected by the pLDH assay. These patients reported treatment with chloroquine in the last 2-5 weeks. Though the immunocapture diagnostic assays may be helpful in certain situations, microscopy of thick blood film is still the method of choice in diagnosing imported malaria.