Leptospirosis complicated with Guillain Barre syndrome,papillitis and thrombotic thrombocytopenic Purpura; a case report

Background

Leptospirosis is a zoonosis commonly prevalent in tropical countries. Clinical course of leptospirosis varies from mild to severe disease. Here we present a case of leptospirosis complicated with Guillain-Barre Syndrome (GBS), papillitis, and Thrombotic Thrombocytopenic Purpura(TTP).

Case presentation

A 21-year-old Asian male presented with fever, myalgia, oliguria and dyspnoea where he was managed as for leptospirosis complicated with pulmonary haemorrhages and acute renal failure. Leptospirosis was confirmed by Microscopic Agglutination Test(MAT) with a fourfold rise in antibody titre between acute and convalescent serum. The highest antibody titre was against Leptospira antigen serogroup Semaranga (strain Patoc) (1:1280) followed by serogroup Australis (strain Australis) (1:640) and serogroup Autumnalis (strain Bankgkinang) (1:320). Two weeks later he developed blindness, ascending weakness of lower limbs with global areflexia and an acute inflammatory demyelinating polyradiculopathy(AIDP) variant GBS was confirmed with nerve conduction studies. TTP complicated the picture several days later. He was initiated on plasmapheresis where clinical improvement was seen after 14?cycles. He had an incomplete neurological recovery with permanent vision loss but completely recovered from TTP. He also had permanent renal impairment.

Conclusion

Leptospirosis should be suspected and treated empirically in the relevant clinical settings where it can present with an atypical clinical picture as in our case with an acute febrile illness followed by GBS as well as TTP.

     

Leptospira infections in trappers from Ontario

BACKGROUND:

Four trappers presented to the Middlesex-London Health Unit in November, 1997 with similar clinical presentations. All four complained of fever, chills and headache, and three of the four had severe muscle aches. All gave histories of trapping raccoons before the onset of illness. Three of the four men exhibited diagnostic seroconversions to Leptospira grippotyphosa.

OBJECTIVE:

To describe the four suspected cases of leptospira infections and to determine whether raccoons might serve as a reservoir of infection using field studies.

DESIGN:

Raccoon serology were undertaken using the microscopic agglutination test against eight serovars of Leptospira interrogans including L grippotyphosa. Raccoons were trapped using Tomahawk live traps, anaesthetized with intramuscular injection of ketamine and acepromazine, bled by cardiac puncture and released.

RESULTS:

Forty-two raccoons were trapped in Middlesex (n=36) and Kent counties (n=6) from April 25 to May 2, 1998, and 10 (23.8%) of these animals had antibodies to L grippotyphosa.

CONCLUSIONS:

Infections due to L grippotyphosa or a closely related serovar are a risk for trappers in Ontario, and raccoons are a likely reservoir of this bacterium.Key Words: Grippotyphosa, Leptospirosis, Ontario, Raccoons, TrappersLeptospirosis is a bacterial disease that affects most mammals throughout the world (1). The causative agent of leptospirosis, Leptospira interrogans, has many serovars, several of which have been isolated in Canada. Although these serovars have been shown to infect many species of wild and domestic animals, human infection occurs only rarely.Human infection has primarily been considered to be an occupational hazard affecting farmers, abattoir workers and others whose occupations involve contact with animals (1). However, recreational activities such as swimming, canoeing, kayaking, biking, and hunting, and contact with pet dogs, domesticated livestock, rodent infestation and rainwater catchment systems in household environments have recently been identified as additional risk factors (2). A large outbreak of leptospirosis occurred in athletes participating in a triathlon in Illinois in the summer of 1998, likely linked to swimming in Lake Springfield (3).In 1997, three confirmed and one suspected case of leptospirosis were recognized in trappers in Middlesex County, Ontario. Presumptive evidence suggested possible transmission to the trappers via contact with raccoons. This paper describes the clinical presentation and laboratory findings of these four individuals and reports studies undertaken to determine whether raccoons in Ontario are infected with L interrogans.     

Antibodies to Leptospira among blood donors in higher-risk areas of Australia: possible implications for transfusion safety

Background

Leptospirosis is one of the most common bacterial zoonoses worldwide, and clinical manifestations range from asymptomatic infection to acute febrile illness, multi-organ failure and death. Asymptomatic, acute bacteraemia in a blood donor provides a potential for transfusion-transmission, although only a single such case from India has been recorded. Human leptospirosis is uncommon in developed countries; however, the state of Queensland in Australia has one of the highest rates among developed countries, especially after increased rainfall. This study examined the prevalence of antibodies to Leptospira spp. in blood donors residing in higher-risk areas of Australia, to evaluate the appropriateness of current blood safety guidelines.

Materials and methods

Plasma samples collected from blood donors residing in higher-risk areas of Australia during 2009 and 2011 were included in the study. All samples were tested for the presence of antibodies to 22 leptospiral serovars using the microscopic agglutination test.

Result

No sample had antibody titres suggestive of a current or recent infection, however, seven samples (1.44%, 95% CI: 0.38–2.50%) had titres suggestive of a past infection.

Discussion

This study provides data that may support the appropriateness of current relevant donor selection policies in Australia. Given that the risk profile for leptospirosis is expanding and that the infection is likely to become more prevalent with climate change, this disease may become more of a concern for transfusion safety in the future.     

Pre-surgical medical treatment,a major prognostic factor for long-term remission in acromegaly

Purpose

To determine whether pre-surgical medical treatment (PSMT) using long-acting Somatostatin analogues in acromegaly may improve long-term surgical outcome and to determine decision making criteria.

Methods

This retrospective study included 110 consecutive patients newly diagnosed with acromegaly, who underwent surgery in a reference center (Marseille, France). The mean long-term follow-up period was 51.4?±?36.5 (median 39.4) months. Sixty-four patients received PSMT during 3–18 (median 5) months before pituitary surgery. Remission was defined at early (3 months) evaluation and at last follow-up by GH nadir after oral glucose tolerance test?<?0.4 µg/L and normal IGF-1.

Results

Pretreated and non-pretreated groups were comparable for the main confounding factors except for higher IGF-1 at diagnosis in PSMT patients. Remission rates were significantly different in pretreated or not pretreated groups (61.1% vs. 36.6%, respectively at long-term evaluation). In multivariate analysis, PSMT was significantly linked to 3 months (p?<?0.01) and long-term remission (p?<?0.01). Duration of PSMT was not significantly different in cured or non-cured patients, at both evaluation times. PSMT appeared to be more beneficial for patients with an invasive tumor. No patient with a tumor greater than 18 mm or mean GH level exceeding 35 ng/mL at diagnosis was cured by surgery alone (vs. 8 and 9 patients in the pretreated group, respectively). Patients with PSMT showed more transient mild hyponatremia after surgery.

Conclusions

PSMT significantly improved short and long-term remission in patients with acromegaly, independent of its duration, especially in invasive adenomas.

     

Recent Progress in Genome Editing Approaches for Inherited Cardiovascular Diseases

Purpose of Review

This review describes the recent progress in nuclease-based therapeutic applications for inherited heart diseases in vitro, highlights the development of the most recent genome editing technologies and discusses the associated challenges for clinical translation.

Recent Findings

Inherited cardiovascular disorders are passed from generation to generation. Over the past decade, considerable progress has been made in understanding the genetic basis of inherited heart diseases. The timely emergence of genome editing technologies using engineered programmable nucleases has revolutionized the basic research of inherited cardiovascular diseases and holds great promise for the development of targeted therapies.

Summary

The genome editing toolbox is rapidly expanding, and new tools have been recently added that significantly expand the capabilities of engineered nucleases. Newer classes of versatile engineered nucleases, such as the “base editors,” have been recently developed, offering the potential for efficient and precise therapeutic manipulation of the human genome.

     

Physical,Psychological, Social,and Existential Symptoms in Older Homeless-Experienced Adults: An Observational Study of the Hope Home Cohort

Background

The homeless population in the United States is aging. Aging-associated comorbidities are associated with increased symptoms.

Objective

To describe the prevalence of symptoms among older homeless-experienced adults, analyze factors associated with moderate–high physical symptom burden, and identify symptom clusters.

Design

Cross-sectional analysis within longitudinal cohort study.

Participants

Using population-based sampling from shelters, meal programs, encampments, and a recycling center in Oakland, CA, we recruited homeless adults aged?≥?50 for a longitudinal cohort. This study includes participants who participated in the 18-month follow-up visit.

Main Measures

We assessed physical symptoms using the Patient Health Questionnaire–15 (PHQ-15); psychological symptoms using the Center for Epidemiologic Studies Depression Scale (CES-D), Primary Care PTSD Screen (PC-PTSD), and psychiatric section of the Addiction Severity Index (ASI); loneliness using the Three-Item Loneliness Scale; and regret using a six-item regret scale.

Key Results

Two hundred eighty-three participants (75.6% men and 82.3% African-Americans) completed symptoms interviews. Over a third (34.0%) had moderate–high physical symptom burden. The most prevalent physical symptoms were joint pain, fatigue, back pain, and sleep trouble. Over half (57.6%) had psychological symptoms; 39.6% exhibited loneliness and 26.5% had high regret. In a multivariate model, being a woman (AOR 2.54, 95% CI 1.28–5.03), childhood abuse (AOR 1.88, 95% CI 1.00–3.50), cannabis use (AOR 2.59, 95% CI 1.38–4.89), multimorbidity (AOR 2.50, 95% CI 1.36–4.58), anxiety (AOR 4.30, 95% CI 2.24–8.26), hallucinations (AOR 3.77, 95% CI 1.36–10.43), and loneliness (AOR 2.32, 95% CI 1.26–4.28) were associated with moderate–high physical symptom burden. We identified four symptom clusters: minimal overall (n?=?129), moderate overall (n?=?68), high physical and high psychological (n?=?67), and high physical and low psychological (n?=?17).

Conclusions

Older homeless-experienced adults exhibit a high prevalence of symptoms across multiple dimensions. To reduce suffering, clinicians should recognize the interaction between symptoms and address multiple symptom dimensions.

     

Infection with Leptospira kirschneri Serovar Mozdok: First Report from the Southern Hemisphere

Leptospirosis is a global zoonosis caused by pathogenic Leptospira spp. In this study, we characterized two Leptospira kirschneri serogroup Pomona serovar Mozdok isolates, one obtained from a dog and the other from a patient with severe leptospirosis, 4 years later. Histopathological analysis showed that both isolates caused severe tissue damage when used to infect hamsters. While L. kirschneri serogroup Pomona serovar Mozdok is endemic in animals in Europe, there is only one report of human leptospirosis in the literature. Although strains belonging to L. kirschneri serogroup Pomona have been identified in cases of human leptospirosis in Europe, serovar Mozdok has not yet been implicated. The 4-year interval between isolations and the fact that this is the first report of serovar Mozdok as the causative agent of human leptospirosis in the southern hemisphere, demonstrates its epidemiological importance to public health. Moreover, the presence of serovar Mozdok in Brazil has the potential to affect vaccine and diagnostic test development.Leptospirosis is a reemerging zoonotic disease, and the global burden is showing an upward trend. The original estimates in 1999¹ predicted some 500,000 annual cases compared with the latest prediction of 873,000 cases and 49,000 mortalities per year, a 74.6% increase over 15 years.² Accurate laboratory diagnosis continues to be a limiting factor, meaning that the true global burden of leptospirosis is likely to be much higher.³ In Latin America, the prevalence of severe leptospirosis is high (10,000 cases a year) due to the tropical climate and lack of appropriate sanitation.³ Although the city of Pelotas has a subtropical climate, > 50 cases of human leptospirosis per 100,000 inhabitants are reported each year, one of the highest rates in southern Brazil.⁴ The infection rate in Pelotas is higher than the Brazilian average for the same period (3.5/100,000) and other regions with similar climatic conditions (> 10/100,000).⁵At present, there are 10 pathogenic Leptospira spp. classified into > 260 serovars⁶ and Leptospira interrogans, Leptospira borgpetersenii, and Leptospira kirschneri are most commonly associated with human leptospirosis.⁷ In Brazil, L. interrogans serogroup Icterohaemorrhagiae serovars Icterohaemorrhagiae and Copenhageni are the main cause of urban leptospirosis and have been widely studied,³ whereas rural leptospirosis and the associated serovars have been largely neglected. To the best of our knowledge, L. kirschneri serogroup Pomona serovar Mozdok has only been implicated in a case of human leptospirosis in Cuba.⁸ Serovar Mozdok is endemic to Croatia where it is prevalent in wild rodents. Human leptospirosis caused by serogroup Pomona is common in that region and while serovar Mozdok has not been implicated in any human cases,⁹ it is a causative agent of canine leptospirosis in Europe.¹⁰We report the isolation and characterization of two isolates of serovar Mozdok recovered from cases of canine and human leptospirosis in Pelotas, southern Brazil. The canine strain was isolated in 2009 during a municipal dog neutering campaign. Urine samples were aseptically collected from the bladder during ovarian hysterectomy, via aspiration using an insulin 30-G needle and syringe (BD Biosciences, Franklin Lakes, NJ). The urine was immediately inoculated into unsupplemented Ellinghausen-McCullough-Johnson-Harris (EMJH; Difco, Sparks, MD) medium (100 μL urine/5 mL EMJH), incubated for 1 hour and then subcultured into EMJH containing 10% of a commercial supplement (Difco). The dog from which the strain was isolated was asymptomatic and was released after the surgical procedure. The second isolate was obtained from the blood culture of a 56-year-old female patient from a rural area of the city. The patient presented with headache, myalgia, fever, vomiting, fatigue, sleepiness, and arthralgia and reported contact with dogs, rats, pigs, cattle, and flood water. The isolate was cultured in EMJH medium as described for the canine isolate. Both isolates were identified as L. kirschneri by means of secY gene sequencing.¹¹ Multilocus sequence typing (MLST)⁷ further characterized the isolates as L. kirschneri serogroup Pomona serovar Mozdok (ST 117). All sequencing procedures were performed using the paired-end technology on an Illumina Solexa platform (Illumina, San Diego, CA; GenBank accession numbers for sequences are shown in

Preliminary Characterization of Mus musculus–Derived Pathogenic Strains of Leptospira borgpetersenii Serogroup Ballum in a Hamster Model

Human and animal leptospirosis caused by Leptospira spp. belonging to serogroup Ballum has increased worldwide in the past decade. We report the isolation and serologic and molecular characterization of four L. borgpetersenii serogroup Ballum isolates obtained from Mus musculus, and preliminary virulence studies. These isolates are useful for diagnosis of leptospirosis and for epidemiologic studies of its virulence and pathogenic mechanisms.Leptospirosis is the most widespread zoonosis in the world.¹ Over the past decade, leptospirosis has been recognized as an important neglected infectious disease.² In Latin America, Africa, and Asia the prevalence of leptospirosis is higher than in other continent mainly because of environmental conditions and distinct leptospiral reservoir species.³ Pelotas is a subtropical coastal city in southern Brazil and it has an annual incidence of > 50 cases of leptospirosis per 100,000 inhabitants, placing it among the cities with the highest incidence of leptospirosis in the country.⁴Urban leptospirosis is caused mainly by Leptospira interrogans serogroup Icterohaemorrhagiae and L. interrogans serogroup Canicola. Interestingly, the increase in human leptospirosis associated with L. borgpetersenii serogroup Ballum has been reported worldwide. In a study conducted in the Caribbean archipelago of Guadeloupe, results emphasized a dramatic increase in the Ballum serogroup, which became the second most common infecting serogroup after Icterohaemorrhagiae.⁵ The same phenomenon has been observed in other countries. This serogroup has become the second most frequent cause of human leptospirosis in New Zealand⁶ and the third most frequent cause in Portugal.⁷ Furthermore, this serogroup appears to be newly established in Australia.⁸ In Cuba, serogroup Ballum has recently been reported as the main cause of human leptospirosis, leading to its use in two experimental, whole-cell, monovalent vaccines for human use.⁹In nature, animal species such as mice and other rodents can act as reservoirs of Leptospira Ballum.¹⁰ Laboratory animals, especially mice and rats, may be experimentally infected with members of serogroup Ballum. However, they usually do not show clinical disease and leptospires may be excreted intermittently. In hamsters, members of the serogroup Ballum produce hemolytic disease caused mainly by hemolysin activity related to sphingomyelinases.¹¹We report the isolation of four L. borgpetersenii serogroup Ballum strains from Mus musculus. We also report serologic, molecular, and preliminary virulence characteristics of these isolates.Six mice were caught alive in traps left overnight near dwellings in a suburban area of Pelotas, Brazil. The animals were immediately taken to the laboratory where they were humanely killed. Tissue samples were removed aseptically. Excised kidney material was macerated and suspended in liquid Ellinghausen-McCullough-Johnson-Harris medium (without antibiotics) for isolation. All cultures were incubated at 30°C and checked weekly for growth. Four animals had positive cultures (isolates were named 1E, 2E, 3E, and, 4E), which were sub-cultured into liquid Ellinghausen-McCullough-Johnson-Harris medium for serologic and molecular typing.Serogrouping was performed by using a panel of rabbit antisera at the Gonçalo Moniz Research Center (Fiocruz, BA, Brazil) as reported.¹² All isolates were classified as belonging to the Ballum serogroup. Species identification was accomplished by sequencing most of the 16S ribosomal RNA gene, as described.¹³ All isolates were classified as L. borgpetersenii. No molecular or serologic characterization at the serovar level was performed.To determine if the isolates would produce infection in hamster model, groups of four 28-day-old animals were inoculated intraperitoneally with approximately 10⁸ leptospires of each isolate in a final volume of 1 mL. Animals were monitored daily for appearance of clinical signs. When moribund, they were humanely killed and subjected to necropsy. Kidneys were aseptically removed; one was macerated and suspended in liquid medium for re-isolation and the other was fixed in formalin buffer for histopathologic analysis. Animal procedures carried out in this study were reviewed and approved by the Committee for Animal Care and Use of Universidade Federal de Pelotas.All isolates caused clinical signs, including evidence of dehydration, ruffled hair coat, decreased activity and isolation, within seven days of inoculation, and death shortly afterwards. Necropsy showed few pathologic findings in animals inoculated with isolates 1E, 2E, and 3E. However, isolate 4E produced severe lesions, with petechial hemorrhages in the lungs (Figure 1A), and jaundice. Staining with hematoxylin and eosin showed alveolar hemorrhage (Figure 1B) and nephritis. Staining with silver showed leptospires in the kidney (Figure 1C).Open in a separate windowFigure 1.Histopathologic findings of leptospirosis in hamster tissue after intraperitonial inoculation with 10⁸ strain 4E leptospires. A, Petequial hemorrhages in the lungs (arrows) of hamsters seven days after infection. B, Prominent focal pulmonary hemorrhage in the lung (arrows) (hematoxylin and eosin stained). C, Hamster kidney tissue seven days after infection showing renal tubules with presence of Leptospira (arrows) (silver stained).Samples from four of six captured animals produced positive cultures, indicating a high prevalence and risk of transmitting the disease to humans and other animals. All four isolates were obtained from the same area, host species, and period, but one of them, isolate 4E, exhibited a more aggressive pattern within the animal model of infection. Similar findings were observed for L. borgpetersenii isolates L550 and JB197, which belong to serovar Hardjo and have distinct phenotypes and virulence.¹⁴ Comparative genomic analysis of their genome sequences showed frameshift and point mutations that might be associated with different capacities to infect hamsters.¹⁵ This finding suggests that the L. borgpetersenii serogroup Ballum isolates describes in this study may represent distinct clonal subtypes. Further genetic analyses and serotyping will be required to fully characterize our isolates.The recent increase in the number of cases of leptospirosis caused by leptospires of serogroup Ballum may be related to vaccination programs. Most veterinary vaccines do not include serogroup Ballum in their preparation. Vaccination may result in suppression of serogroups present in the vaccine, permitting less common species and serogroups to emerge. The same phenomenon occurs in humans, as was the case in Cuba.⁹We recently reported isolation and characterization of seven leptospiral strains belonging to L. interrogans and L. noguchii from human and animal species from southern Brazil.^12,16 The isolates obtained in this study will be used in similar experiments, enabling these isolates to be used in future studies of immunoprotection in the hamster model.In summary, we have characterized four new isolates of L. borgpetersenii serogroup Ballum with various degrees of virulence. One of the isolates was highly virulent in the hamster model and caused pulmonary hemorrhage. Further characterization of these isolates is underway and may help to understand virulence and pathogenic mechanisms of Leptospira spp.     

Quasi-resonant circulation regimes and hemispheric synchronization of extreme weather in boreal summer

The recent decade has seen an exceptional number of high-impact summer extremes in the Northern Hemisphere midlatitudes. Many of these events were associated with anomalous jet stream circulation patterns characterized by persistent high-amplitude quasi-stationary Rossby waves. Two mechanisms have recently been proposed that could provoke such patterns: (i) a weakening of the zonal mean jets and (ii) an amplification of quasi-stationary waves by resonance between free and forced waves in midlatitude waveguides. Based upon spectral analysis of the midtroposphere wind field, we show that the persistent jet stream patterns were, in the first place, due to an amplification of quasi-stationary waves with zonal wave numbers 6–8. However, we also detect a weakening of the zonal mean jet during these events; thus both mechanisms appear to be important. Furthermore, we demonstrate that the anomalous circulation regimes lead to persistent surface weather conditions and therefore to midlatitude synchronization of extreme heat and rainfall events on monthly timescales. The recent cluster of resonance events has resulted in a statistically significant increase in the frequency of high-amplitude quasi-stationary waves of wave numbers 7 and 8 in July and August. We show that this is a robust finding that holds for different pressure levels and reanalysis products. We argue that recent rapid warming in the Arctic and associated changes in the zonal mean zonal wind have created favorable conditions for double jet formation in the extratropics, which promotes the development of resonant flow regimes.Climatic warming over the 20th century has increased the frequency of extreme heat and heavy rainfall events (1–7). On a global scale, the magnitude of this gradual increase can largely be explained by a slowly warming atmosphere, i.e., by thermodynamic arguments only. Thus, the rise in the number of heat extremes can largely be explained by a shift in the mean to warmer values (4, 5, 8). Likewise, upward trends in annual maximum daily rainfall are consistent with the increase in atmospheric moisture associated with warmer air (1, 2).Global warming is also likely to affect large-scale atmospheric circulation patterns, which potentially could alter the frequency of heat and precipitation extremes on seasonal to subseasonal timescales (9–11). In principle, changes in atmospheric dynamics could cause a disproportionate change in the number and/or intensity of extreme weather events (12–14), beyond what is expected from thermodynamics. Moreover, the magnitude of several recent summer extreme weather events in the Northern Hemisphere midlatitudes cannot be explained by a simple shift in the mean (12, 15, 16). These events, which include high-impact extremes like the European heat wave of 2003 (15), the Russian heat wave and the Pakistan flooding in 2010 (17), and heat waves in the United States in recent years (18), were associated with anomalous circulation patterns characterized by persistent, blocking weather conditions (10, 19–22).     

Lipid testing in infectious diseases: possible role in diagnosis and prognosis

Introduction

Acute infections lead to significant alterations in metabolic regulation including lipids and lipoproteins, which play a central role in the host immune response. In this regard, several studies have investigated the role of lipid levels as a marker of infection severity and prognosis.

Scope of review

We review here the role of lipids in immune response and the potential mechanisms underneath. Moreover, we summarize studies on lipid and lipoprotein alterations in acute bacterial, viral and parasitic infections as well as their diagnostic and prognostic significance. Chronic infections (HIV, HBV, HCV) are also considered.

Results

All lipid parameters have been found to be significantly dearranged during acute infection. Common lipid alterations in this setting include a decrease of total cholesterol levels and an increase in the concentration of triglyceride-rich lipoproteins, mainly very low-density lipoproteins. Also, low-density lipoprotein cholesterol, apolipoprotein A1, low-density lipoprotein cholesterol and apolipoprotein-B levels decrease. These lipid alterations may have prognostic and diagnostic role in certain infections.

Conclusion

Lipid testing may be of help to assess response to treatment in septic patients and those with various acute infections (such as pneumonia, leptospirosis and others). Diagnostically, new onset of altered lipid levels should prompt the clinician to test for underlying infection (such as leishmaniasis).

     

Illnesses Associated with Freshwater Recreation During International Travel

Purpose of Review

International travel, adventure travel, and eco-tourism are increasing over the past few decades. This review aims to summarize the spectrum of infections associated with recreational freshwater activities and international travel.

Recent Findings

Recreational water activities can be associated with a wide range of infections. Acute febrile illnesses due to leptospirosis and schistosomiasis are not uncommon in travelers following extensive freshwater exposure. Aeromonas and other water-associated pathogens are important to consider in a traveler presenting with a skin and soft tissue infection. Recreational water activities are often associated with diarrheal illnesses, especially in children, and the range of enteric pathogens includes bacterial pathogens such as Escherichia coli O157:H7 and Shigella species and the protozoan parasites Cryptosporidium and Giardia duodenalis. Infections due to free-living amebas though rare can lead to fulminant central nervous system infections.

Summary

A diverse range of infections may be associated with freshwater exposure, and it is important that these entities are considered in a returning traveler presenting with an acute illness.

     

Adalimumab in severe and acute sciatica: A multicenter,randomized, double‐blind,placebo‐controlled trial

Objective

Based on several experimental results and on a preliminary study, a trial was undertaken to assess the efficacy of adalimumab, a tumor necrosis factor α inhibitor, in patients with radicular pain due to lumbar disc herniation.

Methods

A multicenter, double‐blind, randomized controlled trial was conducted between May 2005 and December 2007 in Switzerland. Patients with acute (duration of <12 weeks) and severe (Oswestry Disability Index score of >50) radicular leg pain and imaging‐confirmed lumbar disc herniation were randomized to receive as adjuvant therapy either 2 subcutaneous injections of adalimumab (40 mg) at 7‐day intervals or matching placebo. The primary outcome was the score for leg pain, based on a visual analog scale (0–100 mm), which was recorded every day for 10 days and at 6 weeks and 6 months.

Results

Of the 265 patients screened, 61 were enrolled; 31 patients were assigned to receive adalimumab, and 4 patients in the placebo group were lost to followup. Over time, the course of leg pain was more favorable in the adalimumab group than in the placebo group (P = 0.002). However, the effect size was relatively small, and at the last followup visit the difference was 13.8 (95% confidence interval −11.5, 39.0). Compared with patients in the placebo group, approximately twice as many patients in the adalimumab group fulfilled the criteria for “responders” and for “low residual disease impact” (P < 0.05), and fewer surgical discectomies were performed (6 versus 13 in the placebo group; P = 0.04).

Conclusion

The addition of a short course of adalimumab to the treatment regimen of patients experiencing acute and severe sciatica resulted in a small decrease in leg pain and in significantly fewer surgical procedures.

     

Clinical manifestations of dengue and leptospirosis in children in Mumbai: an observational study

Objectives  

The aim of this study was to determine the causes of acute febrile illness in children presenting to our hospital following an extremely heavy rainfall event in the city of Mumbai in 2005. The clinical and laboratory manifestations of leptospirosis and dengue together with their outcomes are also described.     

Higher sea surface temperature in the Indian Ocean during the Last Interglacial weakened the South Asian monsoon

Addressing and anticipating future South Asian monsoon changes under continuing global warming is of critical importance for the food security and socioeconomic well-being of one-quarter of the world’s population. However, climate model projections show discrepancies in future monsoon variability in South Asian monsoon domains, largely due to our still limited understanding of the monsoon response to warm climate change scenarios. Particularly, climate models are largely based on the assumption that higher solar insolation causes higher rainfall during similar warm climatic regimes, but this has not been verified by proxy data for different interglacial periods. Here, we compare Indian summer monsoon (ISM) variability during the Last Interglacial and Holocene using a sedimentary leaf wax δD and δ¹³C record from the northern Bay of Bengal, representing the Ganges–Brahmaputra–Meghna (G-B-M) river catchment. In combination with a seawater salinity record, our results show that ISM intensity broadly follows summer insolation on orbital scales, but ISM intensity during the Last Interglacial was lower than during the Holocene despite higher summer insolation and greenhouse gas concentrations. We argue that sustained warmer sea surface temperature in the equatorial and tropical Indian Ocean during the Last Interglacial increased convective rainfall above the ocean but dampened ISM intensity on land. Our study demonstrates that besides solar insolation, internal climatic feedbacks also play an important role for South Asian monsoon variability during warm climate states. This work can help to improve future climate model projections and highlights the importance of understanding controls of monsoonal rainfall under interglacial boundary conditions.

The South Asian monsoon, also known as Indian summer monsoon (ISM), is one of the world’s most sensitive weather systems (1, 2). It is also one of the most critical weather systems for human livelihood. The water and food security of billions of people on the Indian subcontinent and adjacent areas is under pressure by increased weather anomalies and extreme monsoonal rainfall events (1). Despite the far-reaching consequences, prediction of ISM behavior under climate warming scenarios remains a key challenge for both global and regional climate models (3–5). Due to inconsistencies in model projections, debates center on whether the ISM will weaken or strengthen in a warming climate (2–4, 6). In this regard, a major challenge is our incomplete understanding of the extent to which ISM intensity responds to rapidly changing climatic factors—such as rising sea surface temperature (SST), elevated atmospheric greenhouse gas (GHG) concentrations, changing vegetation cover, and decreasing ice sheets and sea ice cover—and their interactive dynamics in a warming climate (1, 2, 5, 7, 8). Several proxy records from stalagmites and marine sediment archives on and around the Indian subcontinent have extended instrumental records and helped to identify monsoon response and variability to various climate forcings (9–12). However, these studies have mainly focused on distinct climatic transitions, namely, between glacial and interglacial periods. While studies showed that the monsoon was generally stronger during warm interglacials and interstadials compared to cold glacials and stadials, the varying degree of monsoonal rainfall intensity between different warm periods—when climatic boundary conditions were fairly similar—is often overlooked. Obtaining and comparing climatic information from different warm periods is therefore highly relevant for constraining uncertainties in model projections for a future warming climate (13).At orbital time scales, changes in incoming solar insolation are regarded the most prominent control for the difference between overall glacial and interglacial monsoon rainfall intensity because past fluctuations of monsoon strength coincide remarkably well with changes in the Earth’s precessional cycle (5, 8, 9, 14–17). Higher summer insolation leads to enhanced atmospheric humidity, wind circulation, and land–sea thermal gradients, which ultimately increase precipitation (8, 18). Although it is generally assumed that higher insolation during warmer interglacials also results in higher ISM rainfall intensity, solar modulation of monsoon intensity and variation during different interglacials has remained largely unexplored. The last interglacial period, commonly correlated with marine isotope stage (MIS) 5e, can be considered a good analog for future climate scenarios because ice sheets at that time were much smaller, while temperatures and sea level were higher than at present (19–21). Compared to the Last Interglacial, the present interglacial period, the Holocene, also underwent comparable changes in orbital configurations, although the magnitude of boreal summer insolation change was weaker at precessional perihelion conditions (22, 23). Because of the higher boreal summer insolation and global SST (by 1 to 2 °C) and the lower ice volume during the Last Interglacial than during the Holocene (24, 25), fully coupled global ocean–atmosphere climate models predict higher monsoon rainfall intensity during the Last Interglacial (ca. 130 to 115 ka) compared to the Holocene (11.6 ka to present) (13, 17, 18). However, despite such model predictions, no direct evidence for higher ISM intensity during the Last Interglacial than during the Holocene has been presented so far.Last Interglacial rainfall reconstructions for the Bay of Bengal branch of the ISM are typically based on stalagmite stable oxygen isotope (δ¹⁸O) records, which show varying magnitudes of δ¹⁸O changes at different sites on the Indian subcontinent (9, 11). However, great caution should be taken in equating stalagmite δ¹⁸O values with rainfall amounts because these values can also be influenced by various moisture sources, water circulation through underground networks, and the influence of climatic conditions on stalagmite formation (8, 11, 14, 26). Another qualitative precipitation proxy, δ¹⁸O of planktonic foraminifera, implies that the surface water salinity in the northern Bay of Bengal was slightly lower during the Holocene than during the Last Interglacial (27). This indicates that freshwater input from the catchment of the Ganges–Brahmaputra–Meghna (G-B-M) river system and ultimately ISM rainfall intensity during the Holocene might have been higher or at least similar despite higher insolation and higher SST in the tropical Indian Ocean during the Last Interglacial (27). Since salinity is not a direct measure of the rainfall amount but rather a proxy for freshwater runoff (28, 29), which could also be driven by mountain glacier melt, applying additional hydrological proxies at the same location can help to elucidate differences in ISM intensity between the two interglacial periods (8).To test whether monsoon rainfall was indeed higher during the Last Interglacial than during the Holocene, we provide regional proxy records of ISM rainfall and vegetation changes in the G-B-M river catchment obtained from a marine sediment core from the northern Bay of Bengal that spans the last ∼130 kyr at submillennial-scale resolution for the Holocene and MIS 5e. This sediment core covers the last two interglacial periods and six precessional cycles, allowing us to scrutinize the relationship between insolation and rainfall intensity for the Bay of Bengal branch of the ISM. In particular, we establish records of the stable hydrogen and carbon isotope composition (δD and δ¹³C) of sedimentary leaf wax lipids, namely, long-chain n-alkanes, that have been extracted from the sediments. Studies of modern surface sediments in the northern Bay of Bengal and moisture source modeling, as well as a continuous ∼18-kyr-long marine sediment record, have confirmed that the δD and δ¹³C of long-chain n-alkanes are reliable proxies for ISM rainfall amount and vegetation changes in the G-B-M catchment (10, 30, 31). To complement our compound-specific stable isotope records, we compare these with published proxy data from the same sediment core (27) as well as with other Asian paleomonsoon proxy records.     

Randomized controlled trial of pulse methyl prednisolone × placebo in treatment of pulmonary involvement associated with severe leptospirosis. [ISRCTN74625030]

Background

The lungs are involved in up to 70% of cases of leptospirosis. In the more severe forms-bleeding from the lungs and acute respiratory distress syndrome-the lethality is high. The treatment proposed for leptospirotic pneumonitis includes just care for patients in critical condition. Clinical and experimental studies point to the involvement of immunological mechanisms in the physiopathology of lung damage caused by leptospirosis. The aim of this study is to evaluate pulse treatment with methylprednisolone × placebo for leptospirotic pneumonitis.

Study design

This is a randomized double-blind clinical trial to test the efficacy of pulse treatment with methylprednisolone in patients with leptospirotic pneumonitis, compared with a placebo. The patients are recruited from three hospitals in the city of Recife, in the Brazilian State of Pernambuco. The exclusion criteria include patients aged under 15 years, a history of hypersensitivity to the use of corticosteroids, the presence of active infection of fungal, tuberculous or bacterial origin apart from the infection by leptospira itself, the presence of hemoconcentration or atypical lymphocyte count on admission to hospital, the presence of co-morbidities that could be responsible for the radiological and gasometric alterations used to diagnose leptospirotic pneumonitis, evidence of recent cranial trauma, neurosurgery, peptic ulcer, and participation in another clinical trial. The patients are followed until they are discharged from hospital or die. The intervention consists of endovenous pulse treatment with 1 g methylprednisolone for three consecutive days in the study group and a placebo in the control group. The primary end-point is mortality from leptospirotic pneumonitis. The secondary end-points are: evolution of lung disease; the occurrence of nosocomial respiratory infection; duration of mechanical ventilation; duration of intensive care unit (ICU) stay; duration of hospital stay; occurrence of other infection-related complications; other respiratory complications; and adverse effects of methylprednisolone. The study is designed to recruit 266 patients and has a statistical "power" of 80% to detect a 50% reduction in mortality.

Discussion

Lung involvement in leptospirosis is a serious manifestation, with a high and variable mortality rate. There is still no specific clearly-established treatment. Well-designed studies are needed to pave the way towards development of such a treatment.

     

Effect of warming temperatures on US wheat yields

Climate change is expected to increase future temperatures, potentially resulting in reduced crop production in many key production regions. Research quantifying the complex relationship between weather variables and wheat yields is rapidly growing, and recent advances have used a variety of model specifications that differ in how temperature data are included in the statistical yield equation. A unique data set that combines Kansas wheat variety field trial outcomes for 1985–2013 with location-specific weather data is used to analyze the effect of weather on wheat yield using regression analysis. Our results indicate that the effect of temperature exposure varies across the September−May growing season. The largest drivers of yield loss are freezing temperatures in the Fall and extreme heat events in the Spring. We also find that the overall effect of warming on yields is negative, even after accounting for the benefits of reduced exposure to freezing temperatures. Our analysis indicates that there exists a tradeoff between average (mean) yield and ability to resist extreme heat across varieties. More-recently released varieties are less able to resist heat than older lines. Our results also indicate that warming effects would be partially offset by increased rainfall in the Spring. Finally, we find that the method used to construct measures of temperature exposure matters for both the predictive performance of the regression model and the forecasted warming impacts on yields.The potential impact of global warming and climate change on socioeconomic outcomes has become an important and growing area of scientific study and evaluation. Separate lines of study include quantifying the likely impact of climatic change on measures of civil conflict (1–5) and agricultural land values, profitability, and/or production efficiency (6–22). Both lines of literature continue to measure, discuss, and debate the effects of warming temperature. An issue that has received much attention in both sets of literature is how best to quantify exposure to extreme temperatures. This is an important concern, as many studies rely on historical spatial and temporal variations in weather outcomes to identify the effects of weather extremes. If these historical extremes are not measured correctly, estimates of their impacts will not be credibly identified, thereby raising doubts regarding any climate change projections based on these impacts.Here we use regression analysis to estimate wheat yields as a function of observed weather variables and forecast yield impacts under a variety of weather scenarios. Our main findings are as follows. First, the effect of temperature exposure varies across the September−May growing season, with the biggest drivers of yield loss being freezing temperatures in the Fall and extreme heat in the Spring. Second, the net effect of warming on yields is negative, even after accounting for the benefits of reduced exposure to freezing temperatures. Third, there exists a tradeoff between mean yield and ability to resist extreme heat across varieties, and more-recently released varieties are less able to resist heat than older ones. Fourth, warming effects are partially offset by increased rainfall in the Spring. Fifth, the method used to construct measures of temperature exposure matters for both the predictive performance of the regression model and the forecasted warming impacts.We focus on wheat as it is one of the first domesticated food crops, forms the basic staple food of major civilizations in Europe, West Asia, and North Africa, and is the most widely planted crop globally. With a 2013 harvest of 8 million hectares, the Great Plains of the United States form the largest contiguous area of low-rainfall winter wheat in the world. Five states (Kansas, Oklahoma, Texas, Colorado, and Nebraska) produce nearly all high-quality hard red winter wheat in the United States. In 2013, Kansas production generated 378 million bushels of wheat at a value of 2.8 billion US dollars. Kansas production value represents 15% of all wheat grown in the United States.Our empirical approach uses data that combine variety-specific wheat yield observations with weather data from the exact location of the field trial. This permits two major advances for estimating the relationship between weather and wheat yield: (i) Location-specific weather data purge the results of aggregation bias that might be present in studies that use weather averages (or other aggregates) across space, and (ii) variety-specific yield responses provide information about the impact of climate on a large number of past, present, and future wheat varieties. Ref. 11 discusses limitations of gridded weather data sets, which have been used extensively because there is not often a weather station in each location of interest. Our data avoid the five pitfalls associated with gridded weather datasets (11). In addition, we find that the warming effects estimated using these field trial data are consistent with effects estimated from on-farm yield data, thereby providing external validity for the results presented here.     

Early warm-season mesoscale convective systems dominate soil moisture–precipitation feedback for summer rainfall in central United States

Land–atmosphere interactions play an important role in summer rainfall in the central United States, where mesoscale convective systems (MCSs) contribute to 30 to 70% of warm-season precipitation. Previous studies of soil moisture–precipitation feedbacks focused on the total precipitation, confounding the distinct roles of rainfall from different convective storm types. Here, we investigate the soil moisture–precipitation feedbacks associated with MCS and non-MCS rainfall and their surface hydrological footprints using a unique combination of these rainfall events in observations and land surface simulations with numerical tracers to quantify soil moisture sourced from MCS and non-MCS rainfall. We find that early warm-season (April to June) MCS rainfall, which is characterized by higher intensity and larger area per storm, produces coherent mesoscale spatial heterogeneity in soil moisture that is important for initiating summer (July) afternoon rainfall dominated by non-MCS events. On the other hand, soil moisture sourced from both early warm-season MCS and non-MCS rainfall contributes to lower-level atmospheric moistening favorable for upscale growth of MCSs at night. However, soil moisture sourced from MCS rainfall contributes to July MCS rainfall with a longer lead time because with higher intensity, MCS rainfall percolates into deeper soil that has a longer memory. Therefore, early warm-season MCS rainfall dominates soil moisture–precipitation feedback. This motivates future studies to examine the contribution of early warm-season MCS rainfall and associated soil moisture anomalies to predictability of summer rainfall in the major agricultural region of the central United States and other continental regions frequented by MCSs.

Soil moisture can affect precipitation through many pathways. Wetter-than-normal soils can effectively increase the moist static energy in the planetary boundary layer (PBL) and favor moist convection (1–3). On the other hand, drier-than-surrounding soils can induce mesoscale circulations that converge moisture toward the drier locations and initiate convection (4–8). While the latter mechanism tends to homogenize the spatial variability of soil moisture by inducing rainfall over dry soils, the former pathway can result in persistent wet/dry soil moisture states important at larger spatial scales and longer timescales (9, 10). These contrasting modulations of the spatiotemporal variability of soil moisture by precipitation can affect subsequent rainfall differently through land–atmosphere interactions.Understanding soil moisture–precipitation feedback is important for improving understanding of subseasonal-to-seasonal predictability of precipitation in regions with strong land–atmosphere interactions (11–13). Located in a transitional zone between the arid, western United States and the humid, eastern United States, the central United States is a hotspot of coupling between soil moisture and precipitation in summer when evapotranspiration (ET) responds strongly to soil water availability and affects subsequent PBL development and convection (14–17). Under favorable thermodynamic and dynamical environments, afternoon convection can grow into mesoscale convective systems (MCSs) spanning >100 km and persisting much longer than isolated convection (18). These longer-lasting, propagating systems account for 30 to 70% of warm-season rainfall and over 50% of extreme rainfall in the central United States (19–22).Compared with non-MCS rainfall, which consists mainly of rainfall from isolated deep convection and stratiform rain, MCS rainfall is on average ∼7 times stronger in rain intensity, although it occurs less frequently in space and time (23). Therefore, MCS and non-MCS rainfall have distinct footprints on land surface processes (24). In a warming climate that modulates the atmospheric and terrestrial environments, MCS and non-MCS rainfall may respond differently (25, 26) and manifest different changes in land–atmosphere interactions due to changes in the background conditions (27, 28). The potentially contrasting interactions of MCS and non-MCS rainfall with the changing environments may have implications for water availability in the major agricultural region of the central United States, motivating the need to understand their individual roles in soil moisture–precipitation feedback. Notably, previous land–atmosphere interaction studies mainly consider the total rainfall (9, 10, 29), despite the distinctive spatiotemporal characteristics of its MCS and non-MCS components (23) that may confound soil moisture–precipitation feedback. This study provides evidence that MCS and non-MCS rainfall in the early warm season (April to June) can induce soil moisture anomalies at different space and time scales, distinguishing their impacts on summer (July) MCS and non-MCS rainfall.To reveal the roles of MCS and non-MCS rainfall in soil moisture–precipitation feedback in the central United States, we use a high-resolution (1/8° and hourly) database that associates the observed rainfall at each hour and grid location with MCS versus non-MCS rain events using an MCS tracking algorithm (24, 25, 30). This MCS dataset is combined with a soil moisture dataset derived from high-resolution (4 km) land surface model simulations with numerical tracers to “tag” MCS and non-MCS rainfall separately and track their partitioning into ET, soil moisture storage, and runoff (24). This dataset allows the total soil moisture to be partitioned into soil moisture components sourced from antecedent MCS or non-MCS rainfall. More details on the development of these datasets over the United States are provided in the Materials and Methods section. With these datasets, we spatially determine whether rain occurs preferentially over wetter/drier-than-surrounding soils and temporally determine whether rain occurs preferentially over wetter/drier-than-usual periods. More specifically, the spatial and temporal preferences of soil moisture anomalies for July afternoon (1500 to 2100 local time) and nighttime (2100 to 0300 local time) rainfall are analyzed using different methods (9, 10) to quantify the percentile values of spatial and temporal soil moisture anomalies associated with MCS and non-MCS rainfall events at the subdaily scale. In addition, the lagged effect of soil moisture on ET and rainfall in subsequent pentads is analyzed using a set of land–atmosphere coupling indices (13). The statistical significance of the results is tested against a null hypothesis of no land-driven feedback. The baseline for the null hypothesis is determined using simulation experiments produced by an analytical model of soil moisture responding to randomized rainfall time series (reference SI Appendix, Supplementary Information Text for more details).