Pharmacokinetics of Artesunate Alone and in Combination with Sulfadoxine/Pyrimethamine in Healthy Sudanese Volunteers

Artesunate (AS) in combination with sulfadoxine/pyrimethamine (SP) is the first-line therapy for management of uncomplicated Plasmodium falciparum malaria in Sudan. The objective of this study was to assess the potential impact of SP on the pharmacokinetics of AS and its active metabolite, dihydroartemisinin (DHA), in healthy adults. A single-dose, randomized, open-label, crossover study design with a washout period of three weeks was performed with 16 volunteers. After oral administration of AS alone or in combination with SP, T_max values of AS and DHA were significantly prolonged in the combination group (P < 0.05). However, there was no significant effect on the other pharmacokinetic parameters (P > 0.05). The t_1/2 values of AS and DHA were significantly higher in females than in males (P < 0.05). The present findings suggest that co-administration of SP with AS has no clinically relevant impact on the pharmacokinetics of AS or DHA in healthy persons.     

Bacteraemia post-autologous haematopoietic stem cell transplantation in the absence of antibacterial prophylaxis: a decade’s experience from Lebanon

Purpose

In this study, we assessed the incidence, contributing factors and outcome of prolonged neutropenia above 7 days and of bacteraemia in patients with lymphoma and multiple myeloma who underwent autologous haematopoietic stem cell transplantation (AHSCT) without antibacterial prophylaxis.

Methods

This is a retrospective chart review of 190 adult patients who underwent AHSCT between 2005 and 2015 at a Lebanese hospital.

Results

Neutropenia of 7 days duration and longer was documented in 66% of the patient population. Through univariate analysis, patients with lymphoma were significantly more likely to have prolonged neutropenia (≥?7 days) compared to those with myeloma. Mucositis above grade 3, diarrhoea and fever were more likely to occur in patients with prolonged neutropenia. Bacteraemia was documented in 12.6% of the patients. Total mortality rate was 3.7%, and that attributed to bacteraemia was 12.5% in the bacteraemia subgroup. Among bacterial isolates recovered from clinical specimens (89 isolates), 70% were Gram-negative, of which 57% were fluoroquinolone susceptible. Ninety-five percent of the Gram-negative bacteria causing bacteraemia were susceptible to fluoroquinolones.

Conclusion

Bacterial pathogens causing bacteraemia were still highly susceptible to fluoroquinolones, despite the high prevalence of fluoroquinolone-resistant strains in the general bacterial ecology. Accordingly, the pertinence of fluoroquinolone prophylaxis in the AHSCT setting warrants further investigation. Moreover, continuous surveillance of local antibiograms in this patient population has become a must in an era of preponderant antibiotic resistance.

     

Shear wave elastography of the tibial nerve in healthy subjects

The purpose of this study is to investigate sonoelastographic features of the tibial nerve.The study included 72 tibial nerves in 36 healthy subjects. High resolution ultrasound and Shear wave elastography were used to evaluate the tibial nerve. Cross sectional area and stiffness were measured.The mean cross sectional area of the tibial nerve was 13.4 mm². The mean shear elastic modulus of the tibial nerve in the short axis was 23.3 kPa. The mean shear elastic modulus of the tibial nerve in long axis was 26.1 kPa. The tibial nerve elastic modulus also showed no correlation with cross sectional area neither in the long axis nor short axis. Age, height, weight, and body mass index showed no correlation with tibial nerve elastic modulus in short or long axes.The elastic modulus of the tibial nerve has been determined in healthy subjects and can serve as a reference for future assessment of polyneuropathy.     

The dystrophin gene and cognitive function in the general population

The aim of our study is to investigate whether single-nucleotide dystrophin gene (DMD) variants associate with variability in cognitive functions in healthy populations. The study included 1240 participants from the Erasmus Rucphen family (ERF) study and 1464 individuals from the Rotterdam Study (RS). The participants whose exomes were sequenced and who were assessed for various cognitive traits were included in the analysis. To determine the association between DMD variants and cognitive ability, linear (mixed) modeling with adjustment for age, sex and education was used. Moreover, Sequence Kernel Association Test (SKAT) was used to test the overall association of the rare genetic variants present in the DMD with cognitive traits. Although no DMD variant surpassed the prespecified significance threshold (P<1 × 10⁻⁴), rs147546024:A>G showed strong association (β=1.786, P-value=2.56 × 10⁻⁴) with block-design test in the ERF study, while another variant rs1800273:G>A showed suggestive association (β=−0.465, P-value=0.002) with Mini-Mental State Examination test in the RS. Both variants are highly conserved, although rs147546024:A>G is an intronic variant, whereas rs1800273:G>A is a missense variant in the DMD which has a predicted damaging effect on the protein. Further gene-based analysis of DMD revealed suggestive association (P-values=0.087 and 0.074) with general cognitive ability in both cohorts. In conclusion, both single variant and gene-based analyses suggest the existence of variants in the DMD which may affect cognitive functioning in the general populations.     

Dissociation of the Role of Infralimbic Cortex in Learning and Consolidation of Extinction of Recent and Remote Aversion Memory

Medial prefrontal circuits have been reported to undergo a major reorganization over time and gradually take a more important role for remote emotional memories such as contextual fear memory or food aversion memory. The medial prefrontal cortex, and specifically its ventral subregion, the infralimbic cortex (IL), was also reported to be critical for recent memory extinction of contextual fear conditioning and conditioned odor aversion. However, its exact role in the extinction of remotely acquired information is still not clear. Using postretrieval blockade of protein synthesis or inactivation of the IL, we showed that the IL is similarly required for extinction consolidation of recent and remote fear memory. However, in odor aversion memory, the IL was only involved in extinction consolidation of recent, but not remote, memory. In contrast, only remote retrieval of aversion memory induced c-Fos activation in the IL and preretrieval inactivation of the IL with lidocaine impaired subsequent extinction of remote but not recent memory, indicating IL is necessary for extinction learning of remote aversion memory. In contrast to the effects in odor aversion, our data show that the involvement of the IL in the consolidation of fear extinction does not depend on the memory age. More importantly, our data indicate that the IL is implicated in the extinction of fear and nonfear-based associations and suggest dissociation in the engagement of the IL in the learning and consolidation of food aversion extinction over time.     

Perforation of metastatic melanoma to the small bowel with simultaneous gastrointestinal stromal tumor

The gastrointestinal tract (GIT) is a common site of metastases for malignant melanoma. These metastatic tumors are often asymptomatic. We describe a case of a 58-year-old male who presented with a sudden onset of generalized abdominal pain. The patient's past medical history was significant for lentigo melanoma of the right cheek. Laparotomy was performed and two segments of small bowel, one with a perforated tumor, the other with a non-perforated tumor, were removed. Histology and immunohistochemical staining revealed the perforated tumor to be a metastatic malignant melanoma and the non-perforated tumor was found to be a gastrointestinal stromal tumor (GIST). The patient was discharged 7 d postoperatively. To the best of our knowledge, this is the first reported case in the literature of a simultaneous metastatic malignant melanoma and a GIST. Surgical intervention is warranted in patients with symptomatic GIT metastases to improve the quality of life or in those patients with surgical emergencies.     

CD34+ blood cells accelerate vascularization and healing of diabetic mouse skin wounds

Diabetes is characterized by poor circulation and impaired angiogenesis, which appear to contribute to the frequent skin lesions and poor wound healing common in diabetic patients. Therapies to improve circulation commonly improve wound healing in diabetic patients. Administration of circulating CD34+ cells, cells that can function as endothelial cell progenitors, accelerates blood flow restoration to ischemic limbs of diabetic mice. We have investigated the potential of these cells to accelerate revascularization and healing in full-thickness skin wounds of hypoinsulinemic (streptozotocin-treated) diabetic mice. Wounds were injected with human CD34+ or CD34- peripheral blood mononuclear cells or no cells, and analyzed for vascularity and healing at various times thereafter. Treatment with CD34+ enriched cells decreased wound size by 4 days after treatment, accelerated epidermal healing, and rapidly and dramatically accelerated revascularization of the wounds compared to controls. Initially increased vascularization was mediated principally by an increase in vessel diameter, but later, both an increase in vascular size and number were observed. These findings indicate that blood-derived progenitors may have therapeutic potential in the treatment of skin lesions in the setting of diabetes, and give insights into how bone marrow cells exert their effects on neovascularization.