Comprehensive and long-term outcomes of enzyme replacement therapy followed by stem cell transplantation in children with Gaucher disease type 1 and 3

Background

Gaucher disease (GD) is a lysosomal storage disorder, characterized by hepatosplenomegaly, pancytopenia, bone diseases, with or without neurological symptoms. Plasma glucosylsphingosine (lyso-Gb1), a highly sensitive and specific biomarker for GD, has been used for diagnosis and monitoring the response to treatment. Enzyme replacement therapy (ERT) is an effective treatment for the non-neurologic symptoms of GD. Neuronopathic GD (type 2 and 3) accounts for 60%–70% of the Asian affected population.

Methods

We explored combination therapy of ERT followed by hematopoietic stem cell transplantation (HSCT) and its long-term outcomes in patients with GD type 3 (GD3).

Results

Four patients with GD3 and one with GD type 1 (GD1) underwent HSCT. The types of donor were one matched-related, one matched-unrelated, and three haploidentical. The age at disease onset was 6–18 months and the age at HSCT was 3.8–15 years in the patients with GD3. The latest age at follow-up was 8–22 years, with a post-HSCT duration of 3–14 years. All patients had successful HSCT. Chronic graft-versus-host disease occurred in one patient. The enzyme activities were normalized at 2 weeks post HSCT. Lyso-Gb1 concentrations became lower than the pathological value. All of the patients are still alive and physically independent. Most of them (4/5) returned to school. None of the patients with GD3 had seizures or additional neurological symptoms after HSCT, but showed varying degrees of cognitive impairment.

Conclusions

ERT followed by HSCT could be considered as an alternative treatment for patients with GD3 who have a high risk of fatal neurological progression.     

Alcohol and alkalosis enhance excystation of Opisthorchis viverrini metacercariae

The northeastern region of Thailand has long been known as an endemic area of the human liver fluke infection which is caused by Opisthorchis viverrini. Humans are infected by ingestion of uncooked cyprinoid fish in traditional dishes such as “koi-pla,” “pla-som,” “pla-jom,” and “pla-ra.” To date, the prevalence of this parasite infection remains high because of cultural behavior and local beliefs. The popular misunderstanding among people in this area is that alcohol, lemon juice, and fish sauce can kill the parasites. Thus, they believe that they can eat raw fish without the risk of infection. This study attempts to clarify the effects of ethyl alcohol and acidosis–alkalosis on O. viverrini metacercariae excystation. Metacercariae of O. viverrini were obtained from infected cyprinoid fish in a natural reservoir. Most metacercariae were obtained from small cyprinoid fish. Metacercariae were divided into three experimental groups and were treated with solutions containing four different concentrations of ethyl alcohol, four different concentrations of salt, and a range of acidic/basic pH. Metacercariae excystation was observed at the assigned times, and the data were then analyzed. Salt had no effect on excystation. Interestingly, the optimal conditions for O. viverrini excystation were pH 9 and 25 % ethyl alcohol. The present study suggests that raw fish should not be eaten while drinking alcohol or when consuming other ingredients with pH 9, because both alcohol and pH 9 could induce O. viverrini metacercariae excystation, leading to the early development of parasites in the hepatobiliary system.     

Vancomycin‐resistant enterococci: New threat in renal patients

SUMMARY Vancomycin‐resistant enterococci (VRE) have been increasingly reported in current literature worldwide. The origin of the organisms remains speculative. Overuse of vancomycin and glycopeptide in animal feed for domestic animals may promote VRE proliferation. The contaminated food products may serve as a community reservoir for VRE. VRE could be found in virtually every environmental site as well as in the endogenous flora of the patients. Important risk factors of VRE infection comprise prolonged hospitalization and prior treatment with antibiotics including vancomycin. The modes of VRE transmission are still not clearly established but could be due to both direct: person‐to‐person and indirect transmissions. In renal patients, VRE infections have been mostly reported in continuous ambulatory peritoneal dialysis peritonitis. Some infections are also detected in haemodialysis patients as well as in renal transplantation patients. Selection of the definite antimicrobial treatment of VRE depends on the phenotypes of the resistance. Antimicrobial agents for VRE consist of the more conventional drugs, including chloramphenicol and tetracycline, and the newer ones, such as ramoplanin. Prevention and control of enteroccal infection should be emphasized in all hospitals and these could be successfully carried out by enhanced infection‐control strategies.     

Effect of vanadate in acute metabolic acidosis

Summary: The effect of vanadate on urinary excretion of acid and electrolyte in dogs with hydrochloric acid (HCI)-induced acute metabolic acidosis was studied. Vanadate caused no changes in systemic and renal haemodynamics, blood parameters and net acid excretion (NAE) in the control group. In the acute metabolic acidosis group, metabolic acidosis per se also had no effect on haemodymic parameters. Fractional excretion of bicarbonate was decreased, while NAE was markedly increased. Following vanadate treatment, acute acid-loaded animals showed an increase in mean arterial pressure (MAP), but a decreased glomerular filtration rate and effective renal plasma flow. These animals had reduced NAE compared to that seen with HCI alone. Thus, vanadate impaired the renal adaptive responses to acute metabolic acidosis. the decreased NAE induced by vanadate might be caused by its known inhibitory effect on hydrogen-potassium-adenosine triphosphatase (H-K-ATPase) and sodium-potassium-adenosine triphosphatase (Na-K-ATPase), and by renal vasoconstriction.     

Sex ratio of babies is unchanged after transfer of fast- versus slow-cleaving embryos

Purpose A higher proportion of male offspring has been observed after transferring faster-developing embryos in a number of animal species. Therefore, we evaluated the correlation between the sex ratio of delivered babies and the cleavage stage of transferred embryos in a human IVF-ET program.Methods The sex of infants born (n=104) after transfer of exclusively slower-cleaving 3 cell (n=41) versus exclusively faster-cleaving 4 cell (n=63) embryos was compared. Furthermore, all boys and girls resulting from IVF-ET (n=213) were compared with respect to: the average number of cells in the embryos that were transferred, the embryo with the greatest number of cells in the cohort transferred and the percentage of embryos that were faster cleaving.Results Thirty seven percent (15/41) of infants resulting from the transfer of exclusively slower-growing embryos were girls and 38% (24/36) of the infants from the faster growing embryos were girls (NS). The analysis all 213 babies born after 145 embryo transfer procedures did not suggest any differences in embryo cleavage rates in embryo transfers leading to male versus female infants.Conclusions A greater number of boys born was not observed after transfer of faster-cleaving embryos as has been described in other animal species. The race to be male may not occur until later cleavage divisions or may not occur in the human embryo.Presented at the IXth World Congress on In Vitro Fertilization and Alternate Assisted Reproduction, April 3–7, 1995, Vienna, Austria.     

Indirect immunoperoxidase test for the diagnosis of leptospirosis

Leptospirosis is a widespread zoonotic disease that affects all mammals, including humans, in different parts of the world. Clinical recognition of leptospirosis is challenging, and the definitive serologic diagnosis assay, the microscopic agglutination test (MAT), is time-consuming and difficult to conduct. In this study, an indirect immunoperoxidase (IIP) test to detect Leptospira-specific antibodies in human serum samples was developed. The efficacy of the IIP was compared with the indirect immunofluorescent assay (IFA) and MAT. A total of 368 human serum samples were analyzed by MAT, IFA, and IIP. Using a MAT titer of > or = 1:100 as the gold standard, the sensitivities for the detection of Leptospiral antibodies at a titer of 1:200 were 94.7% by IFA and 93.6% by IIP; specificities were 95.3% by IFA and 94.9% by IIP; and accuracies were 95.1% by IFA and 94.6% by IIP. With a titer of 1:400, the sensitivity, specificity, and accuracy were 86.2%, 98.9%, and 95.7% by IFA, respectively; whereas, for the IIP, the sensitivity was 85.1%, specificity 98.5%, and accuracy 95.1%. A further evaluation of this test with 80 unknown-febrile-disease sera was also included. We found that the sensitivity and specificity of this test were 100% and 76.8%, respectively. Therefore, the IIP test is a potentially valuable tool for the diagnosis of leptospirosis.     

Nitrative and oxidative DNA damage in oral lichen planus in relation to human oral carcinogenesis

Oral lichen planus (OLP) is a chronic inflammatory disease, which has been clinically associated with development to oral cancer. A double immunofluorescence labeling study found that 8-nitroguanine and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) accumulated in oral epithelium in OLP and oral squamous cell carcinoma (OSCC) biopsy specimens, whereas little or no immunoreactivity was observed in normal oral mucosa. Colocalization of 8-nitroguanine and inducible nitric oxide synthase (iNOS) was found in oral epithelium of OLP and OSCC. Immunoreactivity of 3-nitrotyrosine, which is formed by protein tyrosine nitration and is considered to be a biochemical marker for inflammation, was also observed in oral epithelial cells and colocalized with 8-nitroguanine. Accumulation of p53 was more strongly observed in oral epithelium in OSCC than OLP, whereas there was no p53 accumulation in normal oral mucosa. Our findings demonstrate that iNOS-dependent DNA damage in OLP may lead to p53 accumulation in not only OLP but also OSCC. We conclude that the formation of potentially mutagenic DNA lesions including 8-nitroguanine and 8-oxodG may contribute to the development of oral cancer from OLP.     

Viral kinetics in untreated versus treated acute HIV infection in prospective cohort studies in Thailand

Introduction : The extent of viral replication during acute HIV infection (AHI) influences HIV disease progression. However, information comparing viral load (VL) kinetics with and without antiretroviral therapy (ART) in AHI is limited. The knowledge gained could inform preventive strategies aimed at reducing VL during AHI and therapeutic strategies to alter the viral kinetics that may enhance the likelihood of achieving HIV remission. Methods : The analysis utilized VL data captured during the first year of HIV infection from two studies in Thailand: the RV217 study (untreated AHI, 30 participants and 412 visits) and the RV254 study (treated AHI, 235 participants and 2803 visits). Fiebig stages were I/II (HIV RNA+, HIV IgM−) and Fiebig III/IV (HIV IgM+, Western blot‐/indeterminate). Data were modelled utilizing spline effects within a linear mixed model, with a random intercept and slope to allow for between‐subject variability and adjustment for the differences in variability between studies. The number of knots in the quadratic spline basis functions was determined by comparing models with differing numbers of knots via the Akaike Information Criterion. Models were fit using PROC GLIMMIX in SAS v9.3. Results : At enrolment, there were 24 Fiebig I/II and 6 Fiebig III/IV individuals in the untreated group and 137 Fiebig I/II and 98 Fiebig III/IV individuals in the treated group. Overall, the median age was 27.5 years old, most were male (89%), and CRF01_AE was the most common HIV clade (76%). By day 12 (4 days after ART in RV254), the untreated group had a 2.7‐fold higher predicted mean VL level compared to those treated (predicted log VL 6.19 for RV217 and 5.76 for RV254, p = 0.05). These differences increased to 135‐fold by day 30 (predicted log VL 4.89 for RV217 and 2.76 for RV254) and 1148‐fold by day 120 (predicted log VL 4.68 for RV217 and 1.63 for RV254) (p < 0.0001 for both) until both curves were similarly flat at about day 150 (p = 0.17 between days 150 and 160). The VL trajectories were significantly different between Fiebig I/II and Fiebig III/IV participants when comparing the two groups and within the treated group (p < 0.001 for both). Conclusions : Initiating ART in AHI dramatically changed the trajectory of VL very early in the course of infection that could have implications for reducing transmission potential and enhancing responses to future HIV remission strategies. There is an urgency of initiating ART when acute infection is identified. New and inexpensive strategies to engage and test individuals at high risk for HIV as well as immediate treatment access will be needed to improve the treatment of acute infection globally. Clinical Trial Number : NCT00796146 and NCT00796263     

Effect of acupuncture on heart rate variability during prolonged high-intensity training in soccer players

Objective

To investigate the effects of acupuncture therapy compared with sham acupuncture on heart rate variability (HRV) in 24 elite soccer players during 4-week, high-intensity training sessions.