The prevalence and phenotypic range associated with biallelic PKDCC variants

PKDCC encodes a component of Hedgehog signalling required for normal chondrogenesis and skeletal development. Although biallelic PKDCC variants have been implicated in rhizomelic shortening of limbs with variable dysmorphic features, this association was based on just two patients. In this study, data from the 100 000 Genomes Project was used in conjunction with exome sequencing and panel-testing results accessed via international collaboration to assemble a cohort of eight individuals from seven independent families with biallelic PKDCC variants. The allelic series included six frameshifts, a previously described splice-donor site variant and a likely pathogenic missense variant observed in two families that was supported by in silico structural modelling. Database queries suggested that the prevalence of this condition is between 1 of 127 and 1 of 721 in clinical cohorts with skeletal dysplasia of unknown aetiology. Clinical assessments, combined with data from previously published cases, indicate a predominantly upper limb involvement. Micrognathia, hypertelorism and hearing loss appear to be commonly co-occurring features. In conclusion, this study strengthens the link between biallelic inactivation of PKDCC and rhizomelic limb-shortening and will enable clinical testing laboratories to better interpret variants in this gene.     

Survival in hepatitis C and HIV co-infection: a cohort study of hospitalized veterans.

BACKGROUND & AIMS: Previous studies reported increased morbidity and mortality related to liver disease among human immunodeficiency virus (HIV)-infected patients with hepatitis C co-infection. However, the long-term effect of hepatitis C virus (HCV) co-infection on the mortality of HIV-infected patients remains unclear. METHODS: By using national Veterans Affairs (VA) databases, we performed a retrospective cohort study of HIV patients hospitalized between October 1991 and September 2000. Mortality rates and hazard rate ratios (HRRs) for mortality were calculated for the entire cohort as well as after excluding patients with pre-existing liver disease, with follow-up through September 2001 after discharge. Multivariable adjustment for differences in demographics, comorbidities, and HIV disease severity was performed. Separate analyses were performed for patients identified during the highly active antiretroviral therapy (HAART) era. RESULTS: We identified 18,081 patients, of whom 5320 patients had dual HCV/HIV infection and 12,761 patients had HIV monoinfection. The number of deaths per 100 patient-years was 7.33 in the dual infection group and 14.13 in the HIV monoinfection group during 22,054 and 40,655 person-years of follow-up, respectively. The mortality rate ratio between HCV/HIV dual infection and HIV monoinfection was .53. In Cox multiple regression, the dual HCV/HIV infection group had an adjusted HRR for mortality of .55 compared with the HIV monoinfection group (95% CI, .51-.58, P < .0001), after controlling for age, race, sex, year of diagnosis, and HIV disease severity. These findings persisted in several sensitivity analyses. However, in the HAART era, if patients with liver disease at baseline were excluded, the HRR for mortality was .83 (95% CI, .73-.94, P = .003). CONCLUSIONS: Co-infection with hepatitis C is associated with a significant decrease in the mortality of HIV-infected patients. However, this effect was less pronounced during the HAART era.     

Preparation and evaluation of [125I]troxacitabine: L‐nucleoside model of a potential agent for tumor diagnosis and radiotherapy

In this study, the optimization of troxacitabine labeling with iodine‐125 and its biological evaluation were described. Troxacitabine was labeled via direct electrophilic substitution using chloramine‐T as oxidizing agent. The optimum amounts of reactants were: 50 µ g troxacitabine, 75 µ g Chloramine‐T and ～19 kBq carrier free Na¹²⁵I. The labeled troxacitabine was stable for more than 24 h. Results of the in‐vivo evaluation revealed that the new tracer, [¹²⁵I]troxacitabine, tends to localize in tissues with high proliferation rate with preferential accumulation in cancerous tissues. Imaging should be carried at 3 h postinjection. The in vitro cell growth inhibition assay showed that the effect of [¹²⁵I]troxacitabine was stronger than the effect of cold troxacitabine, which strongly suggested that its cytotoxicity was mainly due to radiotoxicity rather than chemotherapeutic activity. The binding assay revealed that [¹²⁵I]troxacitabine uptake by the Ehrlich and the ARAC8C cells was high and that it bounded well to DNA. Copyright © 2010 John Wiley & Sons, Ltd.     

Free flaps for head and neck cancer reconstruction: Does the use of both large cervical vessels as recipient vessels and the employment of end-to-side technique enhance flap survival?

This study specifically investigates whether the use of both large cervical vessels (the external carotid artery and the internal jugular vein) as recipient vessels with end-to-side anastomosis enhance free flap survival in head and neck cancer reconstruction, when compared with the use of other standard smaller neck recipient vessels and end-to-end anastomosis. A total of 84 consecutive patients were included and were divided into two groups (42 in each group) according to the recipient vessels. The overall vessel thrombosis rate was 6% (five of 84 cases) and the overall flap loss rate was 2.4% (two of 84 cases) yielding a flap salvage rate of 60%. Vessel thrombosis occurred in three cases of the smaller vessels group and in two cases of the large cervical vessels group. This was not statistically significant.     

Phenolic Compounds and Bioactivity of Leaves of Mayodendron Igneum Kurz

Four apigenin glycosides were isolated from the ethyl acetate extract of the leaves of Mayodendron igneum Fam.Bignoniaceae. They were identified as apigenin 7-O-glucoside; 6-methoxy apigenin-7-O-glucoside; 6-methoxy apigenin-7-O-rhamnoglucoside and 6-hydroxy apigenin-7-O-rhamnoglucoside. In addition an isoflavone glycoside was isolated, and identified as genistin 5,4‵-methyl ether. Ethanol (80%) extract of Mayodendron igneum leaves exhibited significant anti-inflammatory and analgesic activities. LD₅₀ determination of the extract indicated the safety of the leaves of the plant.     

Conversion of some 2(3H)-furanones bearing a pyrazolyl group into other heterocyclic systems with a study of their antiviral activity

3-(1,3-diphenylpyrazol-4-yl-methylene)-5-aryl-2(3H)-furanones 2 were prepared and converted into a variety of heterocyclic systems of synthetic and biological importance. Benzylamine reacted with the furanones 2; the product was found to depend on the reaction conditions. Thus, at room temperature the open-chain N-benzylamides 3 were obtained, whereas under refluxing conditions the 2(3H)-pyrrolones were obtained. Hydrazine hydrate affected ring opening of the furanones to give the corresponding acid hydrazides 5. The latter products were used as key starting materials for the synthesis of pyridazinones 7 and 8, 1,3,4-oxadiazoles 11 and 13 and 1,2,4-triazoles 12 and 14 all bearing pyrazolyl moiety as a side-chain. Evaluation of antiviral activity of selected examples of the compounds obtained was performed using two viruses: HAV and HSV-1. Some of the tested compounds showed promising activities.