Liposomes Containing Nickel-Bis(dithiolene) Complexes for Photothermal Theranostics.

New thermosensitive liposomes with a phase transition at 42 °C, containing nickel-bis(dithiolene) complexes as efficient and stable photothermal agents, have been formulated and characterized. These liposomes are highly stable and keep their contents at 37 °C for more than 30 days. On the contrary, the mild hyperthermia generated by the nickel-bis(dithiolene) complex under 940 nm NIR irradiation allows for the fine controlled release of the liposome contents, making such liposomes highly suitable for on-demand drug delivery in the human body under NIR laser irradiation. These liposomes can also be directly used, as shown here, as nanoagents for photothermal therapy. In fact, strong cell death can be generated under laser irradiation in the presence of these photothermally active nanocargos containing less than 10% w/w of metal complex. We also demonstrate, for the first time, that nickel-bis(dithiolene) complexes are good photoacoustic agents, generating easily detectable ultrasonic signals directly proportional to the concentration of complexes and the used laser power.

Circulation of respiratory viruses among pilgrims during the 2012 Hajj pilgrimage.

BACKGROUND: The Hajj is the oldest and largest annual mass gathering in the world and may increase the risk of spread of respiratory viruses. METHODS: We performed a prospective survey among a cohort of pilgrims departing from Marseille, France, to Mecca in the Kingdom of Saudi Arabia (KSA) for the 2012 Hajj season. Nasal swabs were collected from participants and tested for 11 respiratory viruses by real-time reverse transcription polymerase chain reaction. RESULTS: Of 165 participants sampled before departing to the KSA, 8 (4.8%) were positive for at least 1 virus (5 rhinovirus, 1 influenza C, 1 adenovirus, and 1 enterovirus). Seventy symptomatic pilgrims underwent additional nasal swabs during their pilgrimage in the KSA, of which 27 (38.6%) were positive for at least 1 virus (19 rhinovirus, 6 influenza A, 1 influenza C, 1 respiratory syncytial virus B, 1 metapneumovirus, 1 adenovirus, and 1 enterovirus). This was significantly higher than the 4.8% who were positive before departing for the KSA (P < .001). Of 154 pilgrims sampled before leaving the KSA, 17 (11%) were positive for at least 1 virus (13 rhinovirus, 3 adenovirus, 2 influenza B, and 1 enterovirus), which was also significantly higher than the percentage of positive pilgrims (4.8%), before departing for the KSA (P = .040). CONCLUSIONS: This study suggests a rapid acquisition of respiratory viruses among pilgrims during their stay in the KSA, most notably rhinovirus, and highlights the potential of spreading these infections in the pilgrims' home countries upon their return.

Eye lens organoids going simple: characterization of a new 3-dimensional organoid model for lens development and pathology.

The ocular lens, along with the cornea, focuses light on the retina to generate sharp images. Opacification of the lens, or cataract, is the leading cause of blindness worldwide. Presently, the best approach for cataract treatment is to surgically remove the diseased lens and replace it with an artificial implant. Although effective, this is costly and can have post-surgical complications. Toward identifying alternate treatments, it is imperative to develop organoid models relevant for lens studies and anti-cataract drug screening. Here, we demonstrate that by culturing mouse lens epithelial cells under defined 3-dimensional (3D) culture conditions, it is possible to generate organoids that display optical properties and recapitulate many aspects of lens organization at the tissue, cellular and transcriptomic levels. These 3D cultured lens organoids can be rapidly produced in large amounts. High-throughput RNA-sequencing (RNA-seq) on specific organoid regions isolated by laser capture microdissection (LCM) and immunofluorescence assays demonstrate that these lens organoids display spatiotemporal expression of key lens genes, e.g. , Jag1 , Pax6 , Prox1 , Hsf4 and Cryab . Further, these lens organoids are amenable to induction of opacities. Finally, knockdown of a cataract-linked RNA-binding protein encoding gene, Celf1 , induces opacities in these organoids, indicating their use in rapidly screening for genes functionally relevant to lens biology and cataract. In sum, this lens organoid model represents a compelling new tool to advance the understanding of lens biology and pathology, and can find future use in the rapid screening of compounds aimed at preventing and/or treating cataract.

Eye Lens Organoids Made Simple: Characterization of a New Three-Dimensional Organoid Model for Lens Development and Pathology.

Cataract, the opacification of the lens, is the leading cause of blindness worldwide. Although effective, cataract surgery is costly and can lead to complications. Toward identifying alternate treatments, it is imperative to develop organoid models relevant for lens studies and drug screening. Here, we demonstrate that by culturing mouse lens epithelial cells under defined three-dimensional (3D) culture conditions, it is possible to generate organoids that display optical properties and recapitulate many aspects of lens organization and biology. These organoids can be rapidly produced in large amounts. High-throughput RNA sequencing (RNA-seq) on specific organoid regions isolated via laser capture microdissection (LCM) and immunofluorescence assays demonstrate that these lens organoids display a spatiotemporal expression of key lens genes, e.g., Jag1, Pax6, Prox1, Hsf4 and Cryab. Further, these lens organoids are amenable to the induction of opacities. Finally, the knockdown of a cataract-linked RNA-binding protein encoding gene, Celf1, induces opacities in these organoids, indicating their use in rapidly screening for genes that are functionally relevant to lens biology and cataract. In sum, this lens organoid model represents a compelling new tool to advance the understanding of lens biology and pathology and can find future use in the rapid screening of compounds aimed at preventing and/or treating cataracts.

Long-term outcomes of isolated superficial vein thrombosis in patients with active cancer.

BACKGROUND: Cancer patients who develop a deep-vein thrombosis (DVT) or a pulmonary embolism (PE) are at higher risk of death than similar cancer patients who do not develop DVT or PE. The impact of isolated superficial venous thrombosis (SVT) (i.e. without DVT or PE) on the prognosis of cancer patients is unknown. METHODS: Data from the OPTIMEV, multicentre, observational study, to compare at 3 years the incidences of death, DVT-PE recurrence and bleeding of cancer patients with objectively confirmed SVT vs. cancer patients with DVT (matched 1:2 on age, sex, cancer stage) and vs. patients with SVT without cancer (matched 1:3 on age and sex). RESULTS: Cancer patients with SVT (n = 34) had a high risk of death (23.2%patient-year(PY)), that was similar to that of cancer patients with DVT (aHR = 1.0[0.6-1.9]) and higher to that of SVT patients without cancer (aHR = 9.0[3.5-23.1]). Cancer patients with SVT received anticoagulants for a median duration of 45 days and had a high risk of DVT-PE recurrence (6.0%PY), similar to that of cancer patients with DVT (adjusted cause-specific HR (aCHR) = 1.5[0.4-5.8]) and higher to that of SVT patients without cancer (aCHR = 2.9[0.7-11.9]). In our population, venous thrombosis on varicose veins was associated with a lower risk of death (aHR = 0.6[0.3-1.0]) and DVT-PE recurrence (aCHR = 0.6[0.2-1.7]). CONCLUSION: Our results suggest that cancer patients with SVT have a poor prognosis, similar to that of patients with cancer-related DVT. The high rate of DVT-PE recurrence suggests that such patients may need longer duration of anticoagulant treatment.

Biocompatible nanoparticles containing hydrophobic nickel-bis(dithiolene) complexes for NIR-mediated doxorubicin release and photothermal therapy.

Biocompatible nanoparticles (NPs) constituted by amphiphilic poly(ethylene glycol)-block-poly(benzyl malate), PEG-b-PMLABe, have been designed for site-specific PhotoThermal Controlled Release (PTCR) of drugs thanks to the presence of a near infra-red (NIR) photothermally active nickel-bis(dithiolene) complex in the inner core of the NPs, together with doxorubicin (Dox). A nanoprecipitation technique was used to prepare well-defined nickel-bis(dithiolene) and nickel-bis(dithiolene)/Dox loaded NPs, which were characterized by dynamic light scattering (DLS), zeta-potential measurements and Transmission Electron Microscopy (TEM). We have shown that the Dox release was effectively controlled by NIR irradiation (long or pulsed NIR laser irradiation). Cytotoxicity experiments on HeLa and MDA-MB-231 cells have shown that the incorporation of more than 10 w% of nickel-bis(dithiolene) complexes does not increase the intrinsic toxicity of the polymer nanoparticles. Finally, the viability of MDA-MB-231 cells was assessed after their incubation, for 24 hours, with empty NPs, Ni4C12 loaded NPs, Dox loaded NPs or Ni4C12/Dox loaded NPs, without or with NIR irradiation. Above all, the results have highlighted that the Ni4C12 loaded NPs after 5 min NIR laser irradiation can induce strong cell death up to 80% at 50 µg mL-1. These results demonstrate that these NPs are good candidates for photothermal therapy.

Pilgrims from Marseille, France, to Mecca: demographics and vaccination status.

A cohort of 461 Hajj pilgrims to Mecca departing from Marseille was surveyed. Most of travelers originated from North Africa and one third were geriatric patients. An overall low rate of vaccination was observed. The proportions of travelers without correct vaccination were 67% for influenza, 70% for tetanus, 75% for diphteria and poliomyelitis, and 87% for pertussis and hepatitis A.

Fine and Clean Photothermally Controlled NIR Drug Delivery from Biocompatible Nickel-bis(dithiolene)-Containing Liposomes.

This work demonstrates that metal-bis(dithiolene) complexes can be efficiently incorporated inside organic nanocarriers and, that under near-infrared (NIR) irradiation, their high photothermal activity can be finely used to release encapsulated drugs on demand. In contrast to gold nanoparticles and other organic NIR dyes, nickel-bis(dithiolene) complexes do not produce singlet oxygen under irradiation, a highly desirable characteristic to preserve the chemical integrity and activity of the loaded drug during the NIR-triggered release from the nanocarriers. Finally, cytotoxicity experiments performed on various cell lines have shown that the incorporation of such metal complexes do not increase the toxicity of the final liposomal formulation. These results offer great promise for the development of innovative biocompatible drug nanocargos that are able to safely deliver their content on demand under NIR laser irradiation. Moreover, this work demonstrates that metal-bis(dithiolene) complexes, owing to their versatility of functionalization and metal complexation, are attractive photothermal agents for the development of original NIR-responsive materials for application not only in biotechnology but also in materials science.

Biochemical and functional characterization of ORF138, a mitochondrial protein responsible for Ogura cytoplasmic male sterility in Brassiceae.

In cytoplasmic male sterility (CMS), original mitochondrial genes contribute to sex determinism by provoking pollen abortion. The function of the encoded proteins remains unclear. We studied the ORF138 protein, responsible for the 'Ogura' CMS, which is both used in hybrid seed production and present in natural populations. We analyzed the biochemical and structural properties of this protein in male-sterile plants and in E. coli. We showed that this protein spontaneously forms dimers in vitro. Truncated variants of the protein, containing either the hydrophobic or the hydrophilic moiety, also spontaneously dimerize. By fractionating mitochondria, we showed that ORF138 was strongly associated with the inner mitochondrial membrane of male-sterile plants. Our results also strongly suggest that ORF138 forms oligomers in male-sterile plant mitochondria. In E. coli, ORF138 was associated with the plasma membrane, as shown by membrane fractionation, and formed oligomers. The production of this protein strongly inhibited bacterial growth, but not by inhibiting respiration. The observed toxic effects required both the hydrophilic and hydrophobic moieties of the protein.

Water-soluble nickel-bis(dithiolene) complexes as photothermal agents.

The remarkable photothermal properties of pegylated nickel-bis(dithiolene) complexes in water can induce cell death under laser irradiation in the near infrared (NIR) region.

Camel milk-associated infection risk perception and knowledge in French Hajj pilgrims.

Cases of brucellosis have been recently reported in Hajj pilgrims following camel milk consumption. With the aim of evaluating French pilgrim's potential risk for raw camel milk-associated diseases, we conducted a knowledge, attitude, and practice study among 331 pilgrims departing to the 2011 Hajj. A proportion of 8.2% have drunk camel milk before, mostly in North Africa (62.9%) and Saudi Arabia (18.5%). A proportion of 13.9% declared they knew that drinking raw camel milk could cause diseases and 40.6% said that they would drink it if offered during the pilgrimage. Given that camel milk consumption in the Middle East is associated with several zoonotic infections in man, we recommend that Hajj pilgrims be cautioned against consuming unpasteurized dairy products.

Demographics, health and travel characteristics of international travellers at a pre-travel clinic in Marseille, France.

With the aim to identify at-risk individuals among a cohort of international travellers, 3442 individuals who sought advice at Marseille travel health centre in 2009 were prospectively included. Demographics, travel characteristics, chronic medical conditions, vaccinations and antimalarial chemoprophylaxis were documented. Chronic medical conditions were reported by 11% of individuals, including hypertension (39%), asthma (20%), thyroid disease (15%) and depression (13%). 4% reported taking a daily medication, and psychotropic and cardiovascular medications were the most commonly used. Older travellers (≥60 years) accounted for 10% of the travellers and the prevalence of chronic medical conditions was 27% in this group. Individuals aged 15 years or less accounted for 13% of the travellers. Age, last minute travel (17%) and neurological and psychiatric diseases were the most frequent factors that influenced Yellow fever vaccination and malaria chemoprophylaxis, with more than one tenth of the travellers reporting at least one risk factor for which adjusted advice may be necessary. Migrants visiting their relatives in their origin country accounted for 14% of travellers and 73% of this group travelled with their family including young children. We demonstrate that a significant proportion of travellers are at-risk (43%) because of their travel conditions (VFR), their age, or their health status, and should be targeted for risk reduction strategies.

Illness in French travelers to Senegal: prospective cohort follow-up and sentinel surveillance data.

OBJECTIVE: To investigate travel-associated illnesses in French travelers to Senegal. METHODS: A prospective cohort follow-up was conducted in 358 travelers recruited at a pre-travel visit in Marseille and compared to data from ill travelers collected from the GeoSentinel data platform in two clinics in Marseille. RESULTS: In the cohort survey, 87% of travelers experienced health complaints during travel, which most frequently included arthropod bites (75%), diarrhea (46%), and sunburns (36%). Severe febrile illness cases, notably malaria and salmonella, were detected only through the surveillance system, not in the cohort follow-up. Food hygiene was inefficient in preventing diarrhea. Arthropod bites were more frequent in younger patients and in patients with pale phototypes. Sunburns were also more frequent in younger patients. Finally, we demonstrate that mild travel-related gastrointestinal symptoms and the lack of arthropod bites are significantly associated with poor observance of antimalarial prophylaxis. CONCLUSIONS: In this study, we suggest the complementary nature of using cohort surveys and sentinel surveillance data. Effective protection of skin from arthropod bites and sun exposure should result in significantly reduced travel-associated diseases in Senegal. Travelers to Senegal should be informed that diarrhea is extremely common despite preventive measures, but it is mild and transitory and should not lead to the disruption of malaria chemoprophylaxis.