Crotoxin, the main toxin of South American rattlesnake (
Crotalus durissus terrificus) venom, was the first snake venom protein to be purified and crystallized. Crotoxin is a heterodimeric ...β-neurotoxin that consists of a weakly toxic basic phospholipase A
2 and a non-enzymatic, non-toxic acidic component (crotapotin). The classic biological activities normally attributed to crotoxin include neurotoxicity, myotoxicity, nephrotoxicity and cardiotoxicity. However, numerous studies in recent years have shown that crotoxin also has immunomodulatory, anti-inflammatory, anti-microbial, anti-tumor and analgesic actions. In this review, we describe the historical background to the discovery of crotoxin and its main toxic activities and then discuss recent structure–function studies and investigations that have led to the identification of novel pharmacological activities for the toxin.
Bhutan implemented a national program for human papillomavirus (HPV) vaccination in 2010 involving girls aged 12 to 18 years and achieving nearly 90% coverage.
To estimate HPV vaccine effectiveness ...in a city in Bhutan.
2 cross-sectional surveys, 2011-2012 and 2018.
2 hospitals in Thimphu, capital of Bhutan.
Sexually active women aged 17 to 29 years: 1445 participants from the baseline survey and 1595 from the repeated survey.
National HPV vaccination program.
HPV was assessed in cervical cell samples by using general primer GP5+/GP6+-mediated polymerase chain reaction. Human papillomavirus types were stratified as vaccine types (HPV6/11/16/18) and nonvaccine types. Age- and sexual behavior-adjusted overall, total, and indirect (herd immunity) vaccine effectiveness (VE) was computed as (1 - HPV prevalence ratio) for HPV among all women and among unvaccinated women.
Between the 2 surveys, the prevalence of HPV vaccine types decreased from 8.3% to 1.4%, whereas the prevalence of nonvaccine types increased from 25.8% to 31.4%. The overall and indirect adjusted VE against vaccine-targeted HPV types was 88% (95% CI, 80% to 92%) and 78% (CI, 61% to 88%), respectively. Among women younger than 27 years, who were targeted by the vaccination program, the overall and indirect adjusted VE was 93% (CI, 87% to 97%) and 88% (CI, 69% to 95%), respectively. No impact on nonvaccine HPV types was detectable.
Hospital-based recruitment; self-reported vaccination status.
In Bhutan, the prevalence of vaccine-targeted HPV types has decreased sharply, providing the first evidence of the effectiveness of a high-coverage national HPV vaccination program in a lower-middle-income country.
Bill & Melinda Gates Foundation.
Urine sampling may offer a less invasive solution than cervical sampling to test for human papillomavirus (HPV) for HPV vaccine impact monitoring.
Paired samples of urine and exfoliated cervical ...cells were obtained for 89 women with history of high-risk (HR) HPV-positive normal cytology in Bhutan. Urine sampling protocol included self-collection of first-void urine immediately into a conservation medium and procedures to optimize DNA yield. Colposcopical abnormalities were biopsied. Two HPV assays were used: a multiplex type-specific PCR (E7-MPG) and a less analytically sensitive GP5+/6+ PCR followed by reverse line blot.
HPV positivity for 21 types common to both assays was similar in urine and cells by E7-MPG (62.9% and 57.3%, respectively, p = 0.32) but lower in urine by GP5+/6+ (30.3% and 40.4%, p = 0.05). HPV6/11/16/18 positivity did not significantly differ between urine and cells by either assay. Sensitivity of urine (using cells as gold standard) to detect 21 HPV types was 80% and 58% for E7-MPG and GP5+/6+, respectively, with specificity 61% and 89%. HPV type distribution in urine and cells was similar, regardless of assay. The 5 detected CIN3+ were HR-HPV positive in cells by both assays, compared to 4 and 3 by E7-MPG and GP5+/6+, respectively, in urine samples.
For the monitoring of vaccine impact, we demonstrate validity of a urine sampling protocol to obtain HPV prevalence data that are broadly comparable to that from cervical cells. However, detection of HPV in urine varies according to assay sensitivity, presumably because low level infections are frequent.
Background
“REACH‐Bhutan” aimed to evaluate the feasibility and clinical performance of a community‐based screening program for cervical cancer in rural Bhutan using self‐collected samples for ...high‐risk human papillomavirus (HR‐HPV) testing.
Methods
In April/May 2016, 2590 women aged 30–60 years were screened across rural Bhutan by providing a self‐collected sample for careHPV testing. All careHPV‐positive women, plus a random sample of careHPV‐negative women, were recalled for colposcopy and biopsy. Self‐samples also underwent GP5+/6+ polymerase chain reaction (PCR)‐based HR‐HPV DNA detection and genotyping. Cross‐sectional screening indices were estimated against histological high‐grade squamous intraepithelial lesions or worse (hHSIL+), including imputation of hHSIL+ in women without colposcopy.
Results
HR‐HPV positivity was 10.2% by careHPV and 14.8% by GP5+/6+ PCR. Twenty‐two cases of hHSIL+ were histologically diagnosed, including one invasive cancer; an additional 7 hHSIL+ were imputed in women without colposcopy. HR‐HPV testing by GP5+/6+ showed higher sensitivity for hHSIL+ (89.7%, 95% CI 72.6–97.8) than careHPV (75.9%, 95% CI 56.5–89.7). Negative predictive value was also slightly higher for GP5+/6+ (99.9%, 95% CI 99.6–100) than careHPV (99.7%, 95% CI 99.4–99.9). Specificity, however, was lower for GP5+/6+ (86.1%, 95% CI 84.6–87.4) than careHPV (90.6%, 95% CI 89.4–91.7), as was positive predictive value (6.9%, 95% CI 4.5–9.9 vs. 8.5%, 95% CI 5.4–12.6). Of 377 HR‐HPV‐positive women by GP5+/6+, 173 (45.9%) were careHPV‐positive, including 54.7% HPV16‐positive and 30.2% HPV18‐positive women.
Conclusions
The final REACH‐Bhutan results show that screening for cervical cancer with self‐collection of samples and HR‐HPV testing, in addition to our previous report of achieving high participation, can also perform well to detect women with hHSIL+.
The final results of REACH‐Bhutan study show that community‐based screening for cervical cancer with self‐collection of samples and HR‐HPV DNA testing can perform well as the initial step to detect and treat women with histologically proven high‐grade cervical lesions HSIL+, even in remote low‐resource settings.
The study aim was to describe human papillomavirus (HPV)‐attributable cancer burden in Rwanda, according to anogenital cancer site, HPV type, age and HIV status. Tissue specimens of cervical, vulvar, ...vaginal, penile and anal cancer diagnosed in 2012–2018 were retrieved from three cancer referral hospitals and tested for high‐risk (HR) HPV DNA. Cervical cancer represented the majority of cases (598 of 738), of which 96.0% were HR‐HPV positive. HPV‐attributable fractions in other cancer sites varied from 53.1% in 81 penile, through 76.7% in 30 vulvar, 83.3% in 24 vaginal, up to 100% in 5 anal cases. HPV16 was the predominant HR‐HPV type in cervical cancer (55.0%), followed by HPV18 (16.6%) and HPV45 (13.4%). HPV16 also predominated in other cancer sites (60–80% of HR‐HPV‐attributable fraction). For cervical cancer, type‐specific prevalence varied significantly by histology (higher alpha‐9 type prevalence in 509 squamous cell carcinoma vs. higher alpha‐7 type prevalence in 80 adenocarcinoma), but not between 501 HIV‐negative and 97 HIV‐positive cases. With respect to types targeted, and/or cross‐protected, by HPV vaccines, HPV16/18 accounted for 73%, HPV31/33/45/52/58 for an additional 22% and other HR‐HPV types for 5%, of HPV‐attributable cancer burden, with no significant difference by HIV status nor age. These data highlight the preventive potential of the ongoing national HPV vaccination program in Rwanda, and in sub‐Saharan Africa as a whole. Importantly for this region, the impact of HIV on the distribution of causal HPV types was relatively minor, confirming type‐specific relevance of HPV vaccines, irrespective of HIV status.
What's new?
Sub‐Saharan Africa suffers the highest cervical‐cancer rates in the world, due in part to a lack of cervical‐cancer screening programs. In 2011, Rwanda initiated a national HPV‐vaccination program, achieving >90% coverage. In this study, the authors characterized the subsequent burden of all forms of anogenital cancer attributable to high‐risk (HR) HPV types, including cervical, anal, etc. These results illustrate the preventive potential of a national HPV‐vaccination program. They also enhance our understanding of the HPV‐attributable fraction of non‐cervical anogenital cancers in sub‐Saharan Africa overall.
To assess residual cervical intraepithelial neoplasia (CIN) 2/3 disease and clearance of high-risk (hr) human papillomavirus (HPV) infections at 6 months after cryotherapy among HIV-positive women.
...Follow-up study.
79 HIV-positive women received cryotherapy for CIN2/3 in Nairobi, Kenya, and underwent conventional cytology 6 months later. Biopsies were performed on high grade cytological lesions and hrHPV was assessed before (cervical cells and biopsy) and after cryotherapy (cells).
At 6 months after cryotherapy CIN2/3 had been eliminated in 61 women (77.2%; 95% Confidence Interval, (CI): 66.4-85.9). 18 women (22.8%) had residual CIN2/3, and all these women had hrHPV at baseline. CD4 count and duration of combination antiretroviral therapy (cART) were not associated with residual CIN2/3. CIN3 instead of CIN2 was the only significant risk factor for residual disease (odds ratio, OR vs CIN2 = 4.3; 95% CI: 1.2-15.0) among hrHPV-positive women after adjustment for age and HPV16 infection. Persistence of hrHPV types previously detected in biopsies was found in 77.5% of women and was associated with residual CIN2/3 (OR = 8.1, 95% CI: 0.9-70). The sensitivity, specificity, and negative predictive value of hrHPV test in detecting residual CIN2/3 were 0.94, 0.36, and 0.96 respectively.
Nearly one quarter of HIV-positive women had residual CIN2/3 disease at 6 months after cryotherapy, and the majority had persistent hrHPV. CD4 count and cART use were not associated with residual disease or hrHPV persistence. The value of hrHPV testing in the detection of residual CIN2/3 was hampered by a low specificity.
Phenylketonuria (PKU) is the most frequent inborn error of metabolism. It is caused by deficiency in the activity of phenylalanine hydroxylase, leading to accumulation of phenylalanine and its ...metabolites. Untreated maternal PKU or hyperphenylalaninemia may result in nonphenylketonuric offspring with low birth weight and neonatal sequelae, especially microcephaly and intellectual disability. The mechanisms underlying the neuropathology of brain injury in maternal PKU syndrome are poorly understood. In the present study, we evaluated the possible preventive effect of the co-administration of creatine plus pyruvate on the effects elicited by phenylalanine administration to female Wistar rats during pregnancy and lactation on some enzymes involved in the phosphoryltransfer network in the brain cortex and hippocampus of the offspring at 21 days of age. Phenylalanine administration provoked diminution of body, brain cortex an hippocampus weight and decrease of adenylate kinase, mitochondrial and cytosolic creatine kinase activities. Co-administration of creatine plus pyruvate was effective in the prevention of those alterations provoked by phenylalanine, suggesting that altered energy metabolism may be important in the pathophysiology of maternal PKU. If these alterations also occur in maternal PKU, it is possible that pyruvate and creatine supplementation to the phenylalanine-restricted diet might be beneficial to phenylketonuric mothers.
Rwanda was the first African country to implement national human papillomavirus (HPV) vaccination (against types HPV6, 11, 16, and 18). In 2011, a school-based catch-up programme was initiated to ...vaccinate girls aged younger than 15 years but it also reached older girls in schools. We aimed to estimate the population-level effect of HPV vaccination on HPV prevalence.
Cross-sectional surveys were done between July, 2013, and April, 2014 (baseline), and between March, 2019, and December, 2020 (repeat), in sexually active women aged 17–29 years at health centres in the Nyarugenge District of Kigali, Rwanda. HPV prevalence was assessed in cervical cell samples collected by a health-care worker in PreservCyt solution (Cytyc, Boxbourough, MA, USA) and tested using a general primer (GP5+ or GP6+)-mediated PCR. Adjusted overall, total, and indirect (herd immunity) vaccine effectiveness was computed as the percentage of HPV detection among all women and among unvaccinated women.
1501 participants completed the baseline survey and 1639 completed the repeat survey. HPV vaccine-type prevalence in participants aged 17–29 years decreased from 12% (173 of 1501) in the baseline survey to 5% (89 of 1639) in the repeat survey, with an adjusted overall vaccine effectiveness of 47% (95% CI 31 to 60) and an adjusted indirect vaccine effectiveness of 32% (9 to 49). Among participants aged 17–23 years, who were eligible for catch-up vaccination, the adjusted overall vaccine effectiveness was 52% (35 to 65) and the adjusted indirect vaccine effectiveness was 36% (8 to 55), with important heterogeneity according to education (overall vaccine effectiveness was 68% 51 to 79 in participants with ≥6 years of school completed and 16% –34 to 47 in those with <6 years) and HIV status (overall vaccine effectiveness was 55% 36 to 69 for HIV-negative participants and 24% –62 to 64 for HIV-positive participants).
In Rwanda, the prevalence of vaccine-targeted HPV types has been significantly decreased by the HPV vaccine programme, most notably in women who were attending school during the catch-up programme in 2011. HPV vaccine coverage and population-level impact is expected to increase in future cohorts who are eligible for routine HPV vaccination at age 12 years.
Bill & Melinda Gates Foundation.
Recent studies have shown that elevated concentrations of unconjugated bilirubin (UCB) may be a protective host factor against the development of noncommunicable diseases (NCDs), whereas low levels ...of UCB are associated with the opposite effect. The results of this European study, in which 2,489 samples were tested for their UCB concentration using high-performance liquid chromatography (HPLC) and additional data from the MARK-AGE database were used for analysis, provide further evidence that elevated UCB concentrations are linked to a lower risk of developing NCDs and may act as a predictive marker of biological aging as individuals with elevated UCB concentrations showed favorable outcomes in metabolic health and oxidative-stress-related biomarkers. These findings underline the significance of studying individuals with moderate hyperbilirubinemia and investigate UCB routinely, also in the setting of aging, since this condition affects millions of people worldwide but has been underrepresented in clinical research and practice until now.
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•Slightly elevated UCB is a protective host factor against the development of NCDs•Humans with elevated UCB had better metabolic health and oxidative stress markers•UCB may act as a predictive biomarker of biological aging
Pathology; Public health; Human metabolism.
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