Frostbite is tissue damage caused by freezing temperatures and constitutes an important cause of morbidity in cold climate zones and high altitude. The direct effects of sub-zero temperatures lead to tissue freezing, electrolyte shifts and pH alterations, microvascular damage, and eventually to cell death. Upon rewarming, inflammatory reperfusion injury and thrombosis may lead to further tissue damage. Several studies and various case reports show that many patients suffer from long-term sequelae such as vasomotor disturbances (associated with susceptibility to refreezing), and neuropathic and nociceptive pain, as well as damage to skeletal structures. There are still many uncertainties regarding the pathophysiology of these sequelae. It has been shown that the transient receptor potential channel (TRP) family plays a role in cold allodynia. Botulinum Toxin type A (BTX-A) injections have been reported to be beneficial in vasomotor and neuropathic disturbances secondary to frostbite. Epidural sympathetic block has been used for short-term treatment of frostbite induced chronic pain. Furthermore, amitriptyline, gabapentinoids, and duloxetine may have some benefits. Frostbite arthritis clinically resembles regular osteoarthritis. In children there is a risk of epiphyseal cartilage damage leading to bone deformities. Despite some promising therapeutic concepts, the scarcity of data on frostbite long-term sequelae in the literature indicates the need of more in-depth studies of this pathology in all its aspects.

Neutrophils are the most abundant leukocytes in human blood. Upon microbial infection, they are massively and rapidly recruited from the circulation to sites of infection where they efficiently kill pathogens. To this end, neutrophils possess a variety of weapons that can be mobilized and become effective within hours following infection. However, several microbes including some Leishmania spp. have evolved a variety of mechanisms to escape neutrophil killing using these cells as a basis to better invade the host. In addition, neutrophils are also present in unhealing cutaneous lesions where their role remains to be defined. Here, we will review recent progress in the field and discuss the different strategies applied by some Leishmania parasites to escape from being killed by neutrophils and as recently described for Leishmania mexicana, even replicate within these cells. Subversion of neutrophil killing functions by Leishmania is a strategy that allows parasite spreading in the host with a consequent deleterious impact, transforming the primary protective role of neutrophils into a deleterious one.

Key points: Acclimatization to hypoxia leads to a reduction in plasma volume (PV) that restores arterial O₂ content. Findings from studies investigating the mechanisms underlying this PV contraction have been controversial, possibly as experimental conditions were inadequately controlled. We examined the mechanisms underlying the PV contraction evoked by 4 days of exposure to hypobaric hypoxia (HH) in 11 healthy lowlanders, while strictly controlling water intake, diet, temperature and physical activity. Exposure to HH‐induced an ∼10% PV contraction that was accompanied by a reduction in total circulating protein mass, whereas diuretic fluid loss and total body water remained unchanged. Our data support an oncotically driven fluid redistribution from the intra‐ to the extravascular space, rather than fluid loss, as the mechanism underlying HH‐induced PV contraction. Extended hypoxic exposure reduces plasma volume (PV). The mechanisms underlying this effect are controversial, possibly as previous studies have been confounded by inconsistent experimental conditions. Here, we investigated the effect of hypobaric hypoxia (HH) on PV in a cross‐over study that strictly controlled for diet, water intake, physical activity and temperature. Eleven males completed two 4‐day sojourns in a hypobaric chamber, one in normoxia (NX) and one in HH equivalent to 3500 m altitude. PV, urine output, volume‐regulating hormones and plasma protein concentration were determined daily. Total body water (TBW) was determined at the end of both sojourns by deuterium dilution. Although PV was 8.1 ± 5.8% lower in HH than in NX after 24 h and remained ∼10% lower thereafter (all P < 0.002), no differences were detected in TBW (P = 0.17) or in 24 h urine volumes (all P > 0.23). Plasma renin activity and circulating aldosterone were suppressed in HH during the first half of the sojourn (all P < 0.05) but thereafter similar to NX, whereas no differences were detected for copeptin between sojourns (all P > 0.05). Markers for atrial natriuretic peptide were higher in HH than NX after 30 min (P = 0.001) but lower during the last 2 days (P < 0.001). While plasma protein concentration was similar between sojourns, total circulating protein mass (TCP) was reduced in HH at the same time points as PV (all P < 0.03). Despite transient hormonal changes favouring increased diuresis, HH did not enhance urine output. Instead, the maintained TBW and reduced TCP support an oncotically driven fluid redistribution into the extravascular compartment as the mechanism underlying PV contraction.

Cutaneous leishmaniasis is a neglected tropical disease, causing a spectrum of clinical manifestations varying from self-healing to unhealing lesions that may be very difficult to treat. Emerging evidence points to a detrimental role for neutrophils during the first hours following infection with many distinct Leishmania species (spp.) at a time when the parasite is in its nonreplicative promastigote form. Neutrophils have also been detected at later stages of infection in unhealing chronic cutaneous lesions. However, the interactions between these cells and the replicative intracellular amastigote form of the parasite have been poorly studied. Here, we show that Leishmania mexicana amastigotes are efficiently internalized by neutrophils and that this process has only a low impact on neutrophil activation and apoptosis. In neutrophils, the amastigotes were found in acidified vesicles. Furthermore, within cutaneous unhealing lesions, heavily infected neutrophils were found with up to 6 parasites per cell. To investigate if the amastigotes could replicate within neutrophils, we generated photoconvertible fluorescent parasites. With the use of flow cytometry imaging and time-lapse microscopy, we could demonstrate that a subset of parasites replicated within neutrophils. Overall, our data reveal a novel role for neutrophils that can act as a niche for parasite replication during the chronic phase of infection, thereby contributing to disease pathology.

Introduction: Our objective was to perform a systematic review of the outcomes of various frostbite treatments to determine which treatments are effective. We also planned to perform meta-analyses of the outcomes of individual treatments for which suitable data were available. Main Body: We performed a systematic review and meta-analyses in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. We searched PubMed, Cochrane Trials, and EMBase to identify primary references from January 1, 1900, to June 18, 2022. After eliminating duplicates, we screened abstracts to identify eligible studies containing information on treatment and outcomes of Grade 2 to 4 frostbite. We performed meta-analyses of groups of articles that provided sufficient data. We registered our review in the prospective registry of systematic reviews PROSPERO (Nr. 293,693). We identified 4,835 potentially relevant studies. We excluded 4,610 studies after abstract screening. We evaluated the full text of the remaining 225 studies, excluding 154. Ultimately, we included 71 articles with 978 cases of frostbite originating from 1 randomized controlled trial, 20 cohort studies and 51 case reports. We found wide variations in classifications of treatments and outcomes. The two meta-analyses we performed both found that patients treated with thrombolytics within 24 h had better outcomes than patients treated with other modalities. The one randomized controlled trial found that the prostacyclin analog iloprost was beneficial in severe frostbite if administered within 48 h. Conclusions: Iloprost and thrombolysis may be beneficial for treating frostbite. The effectiveness of other commonly used treatments has not been validated. More prospective data from clinical trials or an international registry may help to inform optimal treatment.