Estimating the fraction of progeny virions that must incorporate APOBEC3G for suppression of productive HIV-1 infection

AbstractThe contest between the host factor APOBEC3G (A3G) and the HIV-1 protein Vif presents an attractive target of intervention. The extent to which the A3G–Vif interaction must be suppressed to tilt the balance in favor of A3G remains unknown. We employed stochastic simulations and mathematical modeling of the within-host dynamics and evolution of HIV-1 to estimate the fraction of progeny virions that must incorporate A3G to render productive infection unsustainable. Using three different approaches, we found consistently that a transition from sustained infection to suppression of productive infection occurred when the latter fraction exceeded ~0.8. The transition was triggered by A3G-induced hypermutations that led to premature stop codons compromising viral production and was consistent with driving the basic reproductive number, R0, below unity. The fraction identified may serve as a quantitative guideline for strategies targeting the A3G–Vif axis

Feasibility or Experiment on Working Model of Self Balancing Vehicle

The invention discloses a small-sized self-balancing scooter. The small-sized self-balancing scooter comprises a platform, two wheels arranged on the two sides of the platform correspondingly, and a direction control rod arranged on the platform. The small-sized self-balancing scooter further comprises two pedals arranged on the outer sides of the two wheels correspondingly. The pedals are connected with the small-sized self-balancing scooter through hinges. When the small-sized self-balancing scooter is in a non-riding state, the pedals on the outer sides of the wheels can be turned and folded through the hinges, so that the dimension of the scooter in the length direction is greatly reduced. Therefore, the size of the small-sized self-balancing scooter is reduced, and the small-sized self-balancing scooter can be conveniently carried by riders. Meanwhile, tires of the small-sized self-balancing scooter are arranged in a splayed manner, so that the wheel diameter of the wheels is increased on the basis of ensuring the whole size of the scooter, and the obstacle crossing capacity of the scooter is improved

Coxsackievirus B3 infection early in pregnancy induces congenital heart defects through suppression of fetal cardiomyocyte proliferation

Background Coxsackievirus B (CVB) is the most common cause of viral myocarditis. It targets cardiomyocytes through coxsackie and adenovirus receptor, which is highly expressed in the fetal heart. We hypothesized CVB3 can precipitate congenital heart defects when fetal infection occurs during critical window of gestation. Methods and Results We infected C57Bl/6 pregnant mice with CVB3 during time points in early gestation (embryonic day [E] 5, E7, E9, and E11). We used different viral titers to examine possible dose-response relationship and assessed viral loads in various fetal organs. Provided viral exposure occurred between E7 and E9, we observed characteristic features of ventricular septal defect (33.6%), abnormal myocardial architecture resembling noncompaction (23.5%), and double-outlet right ventricle (4.4%) among 209 viable fetuses examined. We observed a direct relationship between viral titers and severity of congenital heart defects, with apparent predominance among female fetuses. Infected dams remained healthy; we did not observe any maternal heart or placental injury suggestive of direct viral effects on developing heart as likely cause of congenital heart defects. We examined signaling pathways in CVB3-exposed hearts using RNA sequencing, Kyoto Encyclopedia of Genes and Genomes enrichment analysis, and immunohistochemistry. Signaling proteins of the Hippo, tight junction, transforming growth factor-β1, and extracellular matrix proteins were the most highly enriched in CVB3-infected fetuses with ventricular septal defects. Moreover, cardiomyocyte proliferation was 50% lower in fetuses with ventricular septal defects compared with uninfected controls. Conclusions We conclude prenatal CVB3 infection induces congenital heart defects. Alterations in myocardial proliferate capacity and consequent changes in cardiac architecture and trabeculation appear to account for most of observed phenotypes

Effect of Microthreads and Platform Switching on Crestal Bone Stress Levels: A Finite Element Analysis

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142288/1/jper2166.pd

Intravenous Sodium Thiosulphate for Calciphylaxis of Chronic Kidney Disease:A Systematic Review and Meta-analysis

Importance: Calciphylaxis is a rare disease with high mortality mainly involving patients with chronic kidney disease (CKD). Sodium thiosulphate (STS) has been used as an off-label therapeutic in calciphylaxis, but there is a lack of clinical trials and studies that demonstrate its effect compared with those without STS treatment. Objective: To perform a meta-analysis of the cohort studies that provided data comparing outcomes among patients with calciphylaxis treated with and without intravenous STS. Data Sources: PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov were searched using relevant terms and synonyms including sodium thiosulphate and calci∗ without language restriction. Study Selection: The initial search was for cohort studies published before August 31, 2021, that included adult patients diagnosed with CKD experiencing calciphylaxis and could provide a comparison between patients treated with and without intravenous STS. Studies were excluded if they reported outcomes only from nonintravenous administration of STS or if the outcomes for CKD patients were not provided. Data Extraction and Synthesis: Random-effects models were performed. The Egger test was used to measure publication bias. Heterogeneity was assessed using the I2test. Main Outcomes and Measures: Skin lesion improvement and survival, synthesized as ratio data by a random-effects empirical Bayes model. Results: Among the 5601 publications retrieved from the targeted databases, 19 retrospective cohort studies including 422 patients (mean age, 57 years; 37.3% male) met the eligibility criteria. No difference was observed in skin lesion improvement (12 studies with 110 patients; risk ratio, 1.23; 95% CI, 0.85-1.78) between the STS and the comparator groups. No difference was noted for the risk of death (15 studies with 158 patients; risk ratio, 0.88; 95% CI, 0.70-1.10) and overall survival using time-to-event data (3 studies with 269 participants; hazard ratio, 0.82; 95% CI, 0.57-1.18). In meta-regression, lesion improvement associated with STS negatively correlated with publication year, implying that recent studies are more likely to report a null association compared with past studies (coefficient = -0.14; P =.008). Conclusions and Relevance: Intravenous STS was not associated with skin lesion improvement or survival benefit in patients with CKD experiencing calciphylaxis. Future investigations are warranted to examine the efficacy and safety of therapies for patients with calciphylaxis.</p

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

A Rare Case of Amyloid Goiter: Ultrasonographic Findings and Thioflavin T Staining

Background: Clinically significant enlargement of the thyroid gland by amyloid deposition is rare. A case study of 22-year-old lady with gradual enlargement of the thyroid gland has been presented. Routine haemological, biochemical test including thyroid function tests were normal. Ultrasonographic findings were nonspecific. Amyloid goiter has to be differentiated from other types of goitre and malignancy. FNAC was found to be suspicious for the presence of amyloid. Special staining with thioflavin T confirmed amyloid deposition

The steinstrasse : A legacy of extracorporeal lithotripsy

Objectives: To determine the causes of steinstrasse and to assess the success of primary ureteroscopic removal using pneumatic lithotripsy. Methods: Three hundred and two patients with urinary stones (242 renal and 60 ureteric) underwent extracor-poreal shock wave lithotripsy treatment using Stonelith electrohydraulic lithotripter from June 1999 to July 2002 in the Department of Urology, Institute of Medical Sci-ences, Banaras Hindu University. Of these, 29(9.6%) de-veloped steinstrasse. There were 23 males and 6 females in the age group of 24-66 years. After ESWL the patients were followed weekly using plain films and ultrasonogra-phy for the 1 st month and thereafter monthly for 2 months. Their radiological appearance was classified into 3 types. Majority of the patients developing steinstrasse had a stone size of 2-3 cm and most of the steinstrasse was found in the lower ureter usually after 6001-9000 shocks at a mean power of> 16 kv. The length of the steinstrasse was 3-4 cm in the majority of patients. Results: Conservative management was successful in 15 patients (51.7%); repeated ESWL in 4 (13.8%). Ureteroscopic removal using pneumatic lithotripsy under i/v sedation was successful in 10(34.5%) patients. Conclusions: Large stone burden (>2 cm) and use of high energies (>16 kv) are leading factors responsible for the development of steinstrasse. Ureteroscopic removal using pneumatic lithotripsy is a definitive and predictable treatment modality with a high success rate

Management of proximal ureteral stones - comparison of outpatient ureterolithotripsy with in-situ shock wave lithotripsy (SWL)

Objectives: The aim of this study is to review the feasi-bility and effectiveness of ureteroscopy with intracorporeal lithotripsy under intravenous sedation on outpatient basis as a primary procedure in patients with proximal ureteral calculi and its comparison with in situ SWL. Methods: From January 2000 to December 2001, 56 patients with proximal ureteral calculi underwent uretero-lithotripsy and 32 patients underwent in situ shock wave lithotripsy (SWL). Ureterolithotripsy was performed with 8.0 Fr Wolf rigid ureteroscope and Swiss Lithoclast on daycare basis. Results: In patients managed with ureterolithotripsy, stone was successfully reached and fragmented in 47(83.93%) patients. Complete stone fragmentation and spontaneous passage occurred in 40 (71.4%)patients with single session. Seven (12.5%) patients required more than one session for complete clearance. JJ stent was required in 13(23.2%) patients. One case of ureteral perforation was managed successfully with JJ stent. In SWL group, 28 (87.5%) patients became stone free at 3 months. Seven-teen patients (53.2%) required retreatment and adjuvant procedure was done in 6 patients (18.7%). Conclusions: Ureterolithotripsy and in situ SWL are equally effective for proximal ureteral stone. Ureterolitho-tripsy for proximal ureteral calculi has high success rate with low morbidity. It can be done safely with intravenous sedation and local anesthesia. Ureteroscopic stone re-moval can be considered as primary approach in patients with proximal ureteral calculi reserving SWL for those who can afford it