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CAFs shape the immunosuppressive microenvironment of pancreatic cancer through the Lin28b-STING Axis.

Cancer-associated fibroblasts comprise diverse functionally distinct cellular subsets, with certain subpopulations exerting pivotal influence in shaping the pancreatic cancer immune microenvironment. Here we show that Lin28b+ cancer-associated fibroblasts contribute to establishing an immunologically cold tumor microenvironment in pancreatic ductal adenocarcinoma. Mechanistically, Lin28b directly binds to STING mRNA and promotes its degradation, thereby suppressing STING expression and downstream type I interferon signaling. Loss of Lin28b in cancer-associated fibroblasts activates the cGAS-STING-interferon signaling cascade, enhancing dendritic cell antigen presentation and CD8+ T cell cytotoxic function. Importantly, genetic inhibition of Lin28b in cancer-associated fibroblasts enhances sensitivity to anti-PD-L1 immune checkpoint blockade therapy. These findings reveal that targeting the Lin28b-STING axis represents a promising therapeutic strategy for overcoming the intrinsic resistance of pancreatic ductal adenocarcinoma to immunotherapy.

Humans↗

Epilepsy due to a destructive brain lesion caused by a scorpion sting.

BACKGROUND: Symptomatic acute epileptic seizures may occur in up to 5% of individuals, especially children, with scorpion stings. The occurrence of a long-lasting brain lesion or the development of epilepsy after a scorpion sting has never been observed. OBJECTIVE: To describe the development of epilepsy secondary to an extensive hemispheric destructive brain lesion after a scorpion sting. PATIENT: A 15-year-old with a moderate global cognitive impairment and a mild left hemiparesis, with seizures occurring approximately once monthly. RESULTS: The mother reported that the patient at the age of 4 years was stung by a brown scorpion, Tityus serrulatus. The patient soon developed local pain and paresthesias followed by diaphoresis and somnolence. Approximately 24 hours after the sting, she began to convulse. She was then taken to a hospital where she achieved suboptimal seizure control, with daily tonic-clonic seizures and left hemiplegia during the following week. During our clinical investigation, her routine electroencephalogram showed the presence of interictal spikes and diffuse slowing in the right brain hemisphere. Magnetic resonance imaging showed a widespread destructive lesion of her right cerebral hemisphere affecting both the cortical and subcortical structures. CONCLUSION: This is a rare illustration of the biological effects of the toxin of T serrulatus concerning its excitotoxicity and the potential to induce a brain lesion of an epileptogenic nature.

Animals↗

The prognostic significance of specific IgG antibodies in insect sting allergy.

Specific IgG antibodies against bee venom and bee venom components were studied in the serum of 40 bee-sting patients, 60 bee keepers, and 31 control subjects. The highest titres were observed in successfully hypothesized patients and in bee keepers. Subclass-typing in bee-sting allergic patients showed the highest antibody levels in subclass IgG2, followed by IgG3, IgG 4 and IgG1. During hyposensitization, a rise in specific IgG antibodies in all subclasses and against bee venom and all its components was found. The allergic reaction to bee stings disappeared with the rise of specific IgG antibodies, as demonstrated by a bee-sting challenge. After 6 months of hyposensitization therapy, the specific IgG antibodies remained above, and the specific IgE antibodies fell below, the pretreatment levels.

Adolescent↗

Acute renal failure following massive attack by Africanized bee stings.

Bee venom is a complex substance, which acts in several tissues. Although severe allergic reactions have occurred after one or more stings, several deaths have been reported without allergic manifestations, emphasizing the toxic effects of massive poisoning. A number of about 500 stings have been considered necessary to cause death by direct toxicity, but as few as 30-50 stings have proved fatal in children. Among the major toxic effects are hemolytic anemia, acute renal failure (ARF), and shock. ARF may be due to a common toxic-ischemic mechanism with hypovolemic or anaphylactic shock, pigment tubulopathy (myoglobinuria and hemoglobinuria), or acute tubular necrosis (ATN) from a direct kidney toxicity of the venom. We present a case of rhabdomyolysis and hemolysis with consequent ARF which developed after about 800 bee stings. The patient recovered completely after peritoneal dialysis.

Acute Kidney Injury↗

Preliminary report: complement activation in wasp-sting anaphylaxis.

The generation of the anaphylatoxin C3a was measured after a wasp-sting challenge in eight patients with previous anaphylactic reactions to wasp stings. Whereas there was no change in C3a in one patient who showed no reaction and only a slight rise in three patients with mild reactions, C3a rose substantially in the four patients with severe anaphylactic reactions. This complement activation is the first in-vitro variable which correlates with the severity of wasp-sting anaphylactic reactions. A role for complement activation in the pathophysiology of wasp-sting anaphylaxis is therefore suggested.

Adult↗

Bee stings of children: when to perform endotracheal intubation?

Hymenoptera stings account for more deaths in United States that any other envenomation. Oropharyngeal stings, although rare, may produce life-threatening airway obstruction by way of localized swelling. We present 4 cases of bee stings in children that necessitated tracheal intubation and mechanical ventilation. Two children had breathing difficulties at admission; the other 2 presented with minimal symptoms but were preventively intubated and mechanically ventilated. Orofacial bee sting victims should be given parenteral treatment with epinephrine, steroids, antihistamines, and inhalational bronchodilators even when they initially present with minimal symptoms, with general anaphylaxis management in large envenomations, as well as immediate endotracheal intubation and mechanical ventilation for at least 24 hours in patients with signs of airway compromise.

Airway Obstruction↗

Multicenter study of emergency department visits for insect sting allergies.

BACKGROUND: An earlier study of food-related anaphylaxis in the emergency department (ED) suggested low concordance with national guidelines for anaphylaxis management. OBJECTIVE: To extend these findings, we performed a chart review study to describe current ED management of insect sting allergy. METHODS: The Multicenter Airway Research Collaboration performed a chart review study in 15 North American EDs. Investigators reviewed 617 charts of patients with insect sting allergy. Patients were identified by using International Classification of Diseases, 9th Revision, codes 989.5 (toxic effect of venom), 995.0 (other anaphylactic shock), and 995.3 (allergy, unspecified). RESULTS: The cohort was 42% female and 61% white, with a mean age of 36+/-19 years. In this cohort, 58% had local reactions, 11% had mild systemic reactions, and 31% had anaphylactic reactions, as defined by multisystem organ involvement or hypotension. Among patients with systemic reactions (mild or anaphylaxis), most (75%) were stung within 6 hours of ED arrival. While in the ED, 69% of systemic reaction patients received antihistamines, 50% systemic corticosteroids, and 12% epinephrine. Almost all systemic reaction patients (95%) were discharged to home. At ED discharge, 27% (95% CI, 22% to 33%) of systemic reaction patients received a prescription for self-injectable epinephrine. Only 20% (95% CI, 15% to 26%) had documentation of referral to an allergist. CONCLUSIONS: Although guidelines suggest specific approaches for the emergency management of insect sting allergy, concordance with these guidelines appears low in patients with a severe insect sting reaction.

Adult↗

Allergic reactions to insect stings: results from a national survey of 10,000 junior high school children in Israel.

BACKGROUND: Insect sting allergy is a medical condition the magnitude of which has not been fully estimated in children. OBJECTIVES: We sought to evaluate the prevalence of insect stings among schoolchildren in Israel, the rate of allergic reactions, and hospital attendance. METHODS: A self-report questionnaire of the International Study of Asthma and Allergies in Childhood was administered to a national sample of schoolchildren aged 13 to 14 years across Israel. Questions regarding insect stings, allergic reactions, and hospital attendance were added. RESULTS: Ten thousand twenty-one questionnaires were available for analysis. Most (56.3%) had been stung at least once in their lifetime. Of these, 20.5% had a large local reaction (LLR), 11.6% had a mild (cutaneous) systemic reaction (MSR), and 4.4% had a moderate-to-severe systemic reaction (SSR); 11.5%, 6.5%, and 2.5% of the study group, respectively. Arabs had significantly more allergic reactions of all 3 types than Jews (P < .0001). On multivariate analysis, LLR was associated with SSR (odds ratio, 6.25; 95% CI, 4.66-8.41) and MSR (odds ratio, 5.15; 95% CI, 4.24-6.25). More than 10% of the children with an LLR only attended a hospital compared with 7.5% of those with an MSR only and 14.5% with an SSR only. CONCLUSIONS: The frequency of reported allergic sting reactions in children might be higher than previously estimated. Arab children reported significantly more allergic reactions than Jews. Hospital attendance does not correlate with the severity of the allergic reaction, and only a minority of children with SSRs are treated in hospital. CLINICAL IMPLICATIONS: The improper care of severe reactions highlights the need for better public and physician education.

Adolescent↗

Epidemiologic study of insect allergy in children. II. Effect of accidental stings in allergic children.

One hundred eighty-one children with non-life-threatening reactions to insect stings and positive venom skin tests were randomized to treatment (53) or no-treatment (128) groups and followed up clinically and immunologically for at least two years to assess the results of accidental stings. Twenty-eight stings in 17 treated patients and 74 stings in 47 untreated children occurred, leading to one mild reaction in a treated patient, and eight in the no-treatment group (P = NS). No reaction was more serious than the original. Based on IgE antibody changes and skin test results, 87% of the untreated children were stung by an insect to which they had clinical sensitivity by skin test. Vespid skin test sensitivity decreased 10-fold or more in both treated (72%) and untreated (44%) children. Of those with increased sensitivity, congruent to 70% had been stung. These data indicate that the incidence of severe reactions on resting is low in insect-allergic children, and that the majority show decreased skin test sensitivity over time.

Adolescent↗

Ant sting mortality in Australia.

We investigated ant sting related fatalities in Australia over the period 1980-1999. Data was obtained from the Australian Bureau of Statistics and state coronial authorities. Six ant sting-related fatalities were identified, five in Tasmania and one in New South Wales. All were males aged between 40 and 80-years-of-age and most (5/6) had prior histories of jumper or bull ant (Myrmecia spp.) venom allergy. However, none of the deceased carried injectable adrenaline and most died within 20 min of a single sting. Significant cardiopulmonary co-morbidities were identified in all cases and, in addition, moderate-severe laryngeal oedema and coronary atherosclerosis was observed in most (4/6) cases at autopsy. Where ascertained, Myrmecia ant venom specific immunoglobulin E antibodies levels were always elevated and fell into two distinct patterns of immunoreactivity. Adult Tasmanian males with a prior history of ant venom allergy and cardiopulmonary co-morbidities are therefore at highest risk of a fatal outcome from ant stings. Deaths may be avoided by the early recognition of anaphylaxis and self-treatment with adrenaline as well as by the development of purified Myrmecia ant venom immunotherapy.

Adult↗

Bee-sting diseases: Who is at risk? What is the treatment?

Many of the large number of people who are stung each year by bees experience frightening systemic reactions, but the vast majority of such reactions are not life-threatening. There is no evidence that the very few who die as a result of a bee sting come from the pool of those who once before sustained a systemic reaction. On the contrary, no reaction at all may be a more ominous predictor of a lethal outcome on a subsequent sting. Death comes about through multiple mechanisms, and not through anaphylaxis alone. Like most cases of sudden death, underlying coronary atherosclerosis appears to be the principal mechanism. External factors that affect mortality include environmental temperature and site of sting. In general, however, because the numbers of deaths are so small, death comes unpredictably, and those at risk have not been identified. Immunotherapy, whether with venom or whole-body extract, has not been proven to prevent death from a bee sting.

Adult↗

Optic neuropathy occurring after bee and wasp sting.

OBJECTIVE: To inform ophthalmologists about bee and wasp sting-related optic neuropathy. DESIGN: Two case reports and literature review. METHODS: Review of two cases, clinical history, laboratory testing, and follow-up. RESULTS: Two cases of bee and wasp sting optic neuritis are described and five additional cases of optic neuritis occurring after Hymenoptera sting are reviewed from the English language literature. These cases share certain characteristics, including acute to subacute onset of symptoms; moderate to severe visual loss followed by significant visual recovery; edematous and hemorrhagic optic discs; and central or cecocentral scotomas. CONCLUSIONS: Acute optic neuropathy may follow Hymenoptera sting to the face.

Adult↗

Catfish stings to the hand.

Catfish skin toxin and the venom from their dorsal and pectoral spines may cause a menacing sting. Although these stings are often innocuous, severe tissue necrosis may occur. The hand is the most common site of catfish stings. Two cases of catfish stings of the hand are presented. In one of these cases gangrene of the long and small fingers developed requiring amputation. Symptoms are caused by hemolytic, dermonecrotic, edema-promoting, vasospastic, and lethal components of the venom and skin toxins. Local or regional anesthesia is administered to relieve pain and vasospasm. Empiric intravenous antibiotics are administered to cover common aquatic organisms. Wounds with progressive worsening of erythema, swelling, pain, or cyanosis should be irrigated to wash out residual toxin, and debrided of any retained spine fragments or necrotic tissue.

Adult↗

Bee sting allergy in beekeepers.

BACKGROUND: Beekeepers are strongly exposed to honey bee stings and therefore at an increased risk to develop IgE-mediated allergy to bee venom. OBJECTIVE: We wondered whether bee venom-allergic beekeepers were different from normally exposed bee venom-allergic patients with regard to clinical and immunological parameters as well as their response to venom immunotherapy. METHOD: Among the 459 bee venom-allergic patients seen over the 5 year period 1987-91, 62 (14%) were beekeepers and 44 (10%) family members of beekeepers. These two groups were compared with 101 normally exposed bee venom-allergic patients matched with the allergic beekeepers for age and sex, regarding clinical parameters, skin sensitivity, specific IgE and IgG antibodies to bee venom as well as safety and efficacy of venom immunotherapy. RESULTS: As expected, allergic beekeepers had been stung most frequently before the first allergic reaction. The three groups showed a similar severity of allergic symptoms following bee stings and had an equal incidence of atopic diseases. Allergic beekeepers showed higher levels of bee venom-specific serum IgG, lower skin sensitivity and lower levels of bee venom specific serum IgE than bee venom-allergic control patients. A negative correlation between number of stings and skin sensitivity as well as specific IgE was found in allergic beekeepers and their family members, while the number of stings was positively correlated with specific IgG in these two groups. Venom immunotherapy was equally effective in the three groups, but better tolerated by allergic beekeepers than the two other groups. The majority of allergic beekeepers continued bee-keeping successfully under the protection of venom immunotherapy. CONCLUSION: The lower level of sensitivity in diagnostic tests and the better tolerance of immunotherapy in allergic beekeepers is most likely related to the high level of specific IgG in this group.

Adult↗

Diffuse alveolar haemorrhage: a rare reaction to insect sting.

Insect stings and subsequent reactions are common occurrences, but life-threatening systemic reactions are rare. Herein, we describe the case of a young man who developed diffuse pulmonary haemorrhage following an insect sting. He had experienced urticarial reactions to insect stings previously. Diffuse pulmonary haemorrhage should be recognized as an uncommon manifestation of severe systemic reaction to insect sting.

Adult↗

Efficacy of serotherapy in scorpion sting: a matched-pair study.

BACKGROUND/OBJECTIVE: Although evidence of scorpion antivenin effectiveness in the clinical setting is lacking, scorpion antivenin is generally considered the only specific treatment for scorpion sting irrespective of its clinical severity. We conducted a matched-pair study to assess the efficacy of systematic administration of scorpion antivenin. METHODS: Among 600 stung patients who participated in a study on the efficacy of high-dose hydrocortisone after scorpion sting, 135 (cases) had been treated with 10 to 20 mL intravenous scorpion antivenin (neutralizing 10 LD50 venom/mL). Controls were matched on disease severity on arrival to the emergency department. The severity of envenomation was graded I or II according to the absence (grade I) or the presence (grade II) of systemic manifestations of scorpion envenomation. Assessment of scorpion antivenin efficacy was based on the rate of changing severity grade in both groups (clinical improvement or worsening during an observation period of at least 4 hours). RESULTS: Both groups were similar with respect to clinical severity (36 patients were graded II in each group), age, sex, time-lapse between scorpion sting and ED arrival, and the administration of adjunctive therapy such as hydrocortisone. By the 4-hour evaluation, 50% and 64% of patients initially graded II exhibited a substantial clinical improvement in cases and controls, respectively, suggesting similar effects in cases and controls. There was no difference in preventive effects: 13% and 10% of cases and controls developed systemic manifestations of scorpion envenomation during the 4-hour observation period; 23% of cases and 17% controls were hospitalized by this time. There was no difference in the duration of hospitalization. Three cases developed anaphylactic shock as a consequence of scorpion antivenin administration, while 1 scorpion antivenin-untreated patient died from refractory shock. CONCLUSION: Systematic administration of scorpion antivenin irrespective of clinical severity did not alter the clinical course of scorpion sting. A prospective study is needed concerning the response of the more severe scorpion envenomations.

Adolescent↗

Randomized controlled trial of topical aspirin in the treatment of bee and wasp stings.

BACKGROUND: The New South Wales Poisons Information Centre (NSW PIC) has been recommending the use of topical aspirin paste for bee and wasp stings since the early 1980s. Anecdotal evidence from calls suggested it was effective in reducing the swelling and duration of pain, but a literature search found no evidence to support this. OBJECTIVE: The objective of this study was to assess the effectiveness of advice given by a PIC to apply topical aspirin for the treatment of bee and wasp stings. METHODS: Patients were recruited from callers to the NSW PIC who reported a bee or wasp sting. They were randomly assigned, using a 2:1 ratio, to two different treatment advices: to apply an ice pack (control group), or to apply an ice pack and topical aspirin paste (treatment group). Initial follow-up was within 24-48 hours. Primary outcome was the presence of swelling at 12 hr. Secondary outcomes included the presence of pain at 12 hr, the presence of itchiness, and duration of redness. RESULTS: There were 37 patients who received treatment advice and 19 in the control group. Of the 37 patients advised to apply aspirin, 21 (57%) had no swelling at 12 hr compared with 14 of the 19 (74%) patients with ice alone (difference -17%; 95% CI: -47-12%; p = 0.26). Eighty-one percent (30/37) of patients advised to apply aspirin had no pain at 12 hr compared with (18/19) 95% of the others (-14%; 95% CI: -39-14%; p = 0.34). The median duration of redness was 6 hr [interquartile range (IQR): 2-48 hr] in those advised to apply aspirin paste compared with 2 hr (IQR: 0-10 hr) in those that only applied ice (p = 0.04). CONCLUSIONS: Topical aspirin paste was not effective in reducing the duration of swelling or pain in bee and wasp stings, and significantly increased the duration of redness. Symptoms rapidly subsided with ice alone as treatment.

Administration, Topical↗

Indoor fire ant sting attacks: a risk for frail elders.

OBJECTIVE: We have previously reported 10 indoor sting attacks by imported fire ants, most of which involved frail elderly people in the Southeastern United States. Since the range of these insects is expanding and attacks often attract media attention, we hypothesized that additional attacks of which we were unaware may have occurred and were reported in local newspapers. METHODS: We searched the archives from 1989 until 2004 of 182 US newspapers in fire ant endemic areas in 10 states. RESULTS: Ten additional cases of indoor fire ant sting attacks were reported in local newspapers between 1991 and 2004. This brings the total to 16 attacks on adults and four on infants. Most adult attacks occurred in long-term care facilities, but three involved hospitalized patients. Morbidity ranged from nightmares to death in seven adults. One of the infants died and two suffered long-term morbidity. Six of the 20 sting victims died within 1 week of the attack. Seven of the 10 attacks reported in newspapers did not result in significant medical consequences, as compared with only two of the 10 attacks in previously published reports. CONCLUSION: Increasing numbers of indoor fire ant sting attacks are occurring in the United States, and frail elderly people and infants are at risk. They should be removed from indoor areas where ants are present until the ants are eradicated.

Adult↗