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RNA binding proteins (RBPs) post-transcriptionally regulate gene expression by associating with regulatory sequences in the untranslated regions of mRNAs. Cold-inducible RBP (CIRP) is a stress-induced RBP that was recently shown to modulate inflammation in response to cellular stress, where it increases or decreases pro-tumorigenic (proinflammatory) cytokines in different contexts. CIRP expression is altered in several cancers, including breast cancer, but the effects of CIRP on inflammation in breast cancer is not known. Here, we investigate if CIRP alters growth and the inflammatory profile of breast tumors. Transgenic mice overexpressing CIRP in the mammary epithelium were crossed with the PyMT mouse model of breast cancer, and the effects on both early and late tumorigenesis and inflammation were assessed. The effects of CIRP knockdown were also assessed in Py2T cell grafts. Overexpression of CIRP led to decreased tumorigenesis in the PyMT mouse model. Conversely, the knockdown of CIRP in Py2T cell grafts led to increased tumor growth. Luminex cytokine assays assessed the effects on the inflammatory environment. CIRP/PyMT mammary glands/mammary tumors and serum had decreased cytokines that promote inflammation, angiogenesis, and metastasis compared to PyMT mammary glands and serum, documenting a shift towards an environment less supportive of tumorigenesis. CIRP overexpression also decreased CD4 + helper T cells and increased CD8 + cytotoxic T cells in mammary tumors. Overall, these data support a role for CIRP as a potent antitumor molecule that suppresses both local and systemic pro-tumorigenic inflammation.

Ionic liquids (ILs) have shown to be promising additives to the catalyst layer to enhance oxygen reduction reaction in polymer electrolyte fuel cells. However, fundamental understanding of their role in complex catalyst layers in practically relevant membrane electrode assembly environment is needed for rational design of highly durable and active platinum-based catalysts. Here we explore three imidazolium-derived ionic liquids, selected for their high proton conductivity and oxygen solubility, and incorporate them into high surface area carbon black support. Further, we establish a correlation between the physical properties and electrochemical performance of the ionic liquid-modified catalysts by providing direct evidence of ionic liquids role in altering hydrophilic/hydrophobic interactions within the catalyst layer interface. The resulting catalyst with optimized interface design achieved a high mass activity of 347 A g -1 Pt at 0.9 V under H 2 /O 2 , power density of 0.909 W cm -2 under H 2 /air and 1.5 bar, and had only 0.11 V potential decrease at 0.8 A cm -2 after 30 k accelerated stress test cycles. This performance stems from substantial enhancement in Pt utilization, which is buried inside the mesopores and is now accessible due to ILs addition., (© 2022. The Author(s).)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Objective: The objective of this study was to determine the relationship between atrophy of the hippocampus and severity of epilepsy in patients with temporal lobe epilepsy (TLE) as the first step to evaluate the possibility of surgery for epilepsy and analyze why patients cannot undergo epilepsy surgery. Methods: Volumetric MRI of the hippocampus was performed in 51 consecutive patients (29 men; mean age 40) with TLE. TLE diagnosis, lateralization, and severity (mild, moderate, severe) of seizures were based on a comprehensive evaluation that included neurologic examination and EEG in all patients. Patients with evidence of a lesion other than hippocampal sclerosis were not included in the study. We assessed the relationship between hippocampal volumes and electrophysiological evidence of seizure severity. Results: According to the affected side based on the EEG, a statistically significant difference ( p < 0.001) in volume and a positive correlation between epilepsy and hippocampal atrophy were found. Conclusion: Our results confirm that volume loss to the hippocampus in patients with TLE correlates with the severity of epilepsy based on the EEG. Therefore, surgical treatment is considered early when hippocampal atrophy is evident in patients with refractory TLE. However, in Latin American countries, it is a challenge to get a patient to undergo epilepsy surgery. Therefore, we try to analyze the sad situation in our hospital., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Rentería-Palomo, Montes-Ochoa, Martinez-Mayorga, Reyes-Vaca and Rodríguez-Leyva.)

The pathogenic mechanisms underlying severe SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection remain largely unelucidated. High-throughput sequencing technologies that capture genome and transcriptome information are key approaches to gain detailed mechanistic insights from infected cells. These techniques readily detect both pathogen- and host-derived sequences, providing a means of studying host-pathogen interactions. Recent studies have reported the presence of host-virus chimeric (HVC) RNA in transcriptome sequencing (RNA-seq) data from SARS-CoV-2-infected cells and interpreted these findings as evidence of viral integration in the human genome as a potential pathogenic mechanism. Since SARS-CoV-2 is a positive-sense RNA virus that replicates in the cytoplasm, it does not have a nuclear phase in its life cycle. Thus, it is biologically unlikely to be in a location where splicing events could result in genome integration. Therefore, we investigated the biological authenticity of HVC events. In contrast to true biological events like mRNA splicing and genome rearrangement events, which generate reproducible chimeric sequencing fragments across different biological isolates, we found that HVC events across >100 RNA-seq libraries from patients with coronavirus disease 2019 (COVID-19) and infected cell lines were highly irreproducible. RNA-seq library preparation is inherently error prone due to random template switching during reverse transcription of RNA to cDNA. By counting chimeric events observed when constructing an RNA-seq library from human RNA and spiked-in RNA from an unrelated species, such as the fruit fly, we estimated that ∼1% of RNA-seq reads are artifactually chimeric. In SARS-CoV-2 RNA-seq, we found that the frequency of HVC events was, in fact, not greater than this background "noise." Finally, we developed a novel experimental approach to enrich SARS-CoV-2 sequences from bulk RNA of infected cells. This method enriched viral sequences but did not enrich HVC events, suggesting that the majority of HVC events are, in all likelihood, artifacts of library construction. In conclusion, our findings indicate that HVC events observed in RNA-sequencing libraries from SARS-CoV-2-infected cells are extremely rare and are likely artifacts arising from random template switching of reverse transcriptase and/or sequence alignment errors. Therefore, the observed HVC events do not support SARS-CoV-2 fusion to cellular genes and/or integration into human genomes. IMPORTANCE The pathogenic mechanisms underlying SARS-CoV-2, the virus responsible for COVID-19, are not fully understood. In particular, relatively little is known about the reasons some individuals develop life-threatening or persistent COVID-19. Recent studies identified host-virus chimeric (HVC) reads in RNA-sequencing data from SARS-CoV-2-infected cells and suggested that HVC events support potential "human genome invasion" and "integration" by SARS-CoV-2. This suggestion has fueled concerns about the long-term effects of current mRNA vaccines that incorporate elements of the viral genome. SARS-CoV-2 is a positive-sense, single-stranded RNA virus that does not encode a reverse transcriptase and does not include a nuclear phase in its life cycle, so some doubts have rightfully been expressed regarding the authenticity of HVCs and the role played by endogenous retrotransposons in this phenomenon. Thus, it is important to independently authenticate these HVC events. Here, we provide several lines of evidence suggesting that the observed HVC events are likely artifactual.

Introduction and Objectives: To characterize the virological features of hepatitis E virus (HEV) in serum from patients exhibiting chronic liver damage., Methods: A data-base of 513 unrelated individuals from West-Mexico with liver-disease determined by clinical and biochemical tests and transient elastography between 2011 and 2016 were retrospectively analyzed. According to infectious etiologies, patients were classified as hepatitis B virus (HBV)-, hepatitis C virus (HCV)-infected patients, and patients exhibiting chronic liver damage with non-identified infectious etiological agent (NIIEA). Available serum samples from NIIEA-patients were tested by RT-nPCR for the presence of HEV-RNA and partially sequenced for genotyping., Results: Out of the 513 cases, 5.85% were patients infected with HBV, 67.64% with HCV, and 26.51% were NIIEA-patients. Among 76 available samples from NIIEA-cases, 30.26% tested positive for HEV-RNA. Twelve (15.79%) partial HEV sequences allowed phylogenetic analysis, revealing the classification of HEV as HEV-Gt3. Advanced fibrosis (F3-F4 stage) was found in a 26.1% of patients with HEV-active infection., Conclusion: Although HCV is the main infectious agent related to chronic liver disease in Mexico, liver damage without an infectious etiology is common. Our findings reveal that an elevated rate of chronic liver disease might be represented by autochthonous infection of HEV-Gt3, whose detection makes Mexico unique in Latin-America with the circulation of HEV strains belonging to three genotypes (Gt1, Gt2, and Gt3). Thus, HEV infection should be a matter of health concern, and mandates for HEV screening to properly handle this commonly undiagnosed disease., (Copyright © 2019 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

Hepatitis A virus (HAV) is the most common cause of acute viral hepatitis worldwide. The virus is mainly transmitted via the fecaloral route and, the incidence of infection is closely related to low socioeconomic conditions and poor sanitation. Mexico, previously categorized an area of high endemicity for HAV infection, is undergoing epidemiological transition. However, a limited number of HAV-related scientific reports regarding to virus burden is available. According to the local government health agency (Secretarla de Salud, SSA in Spanish), from 1994 to 2017 a reduction in the incidence of hepatitis related to HAV has been reported. However, HAV is still the most common cause of viral hepatitis in the country, and the pediatric population is the most prone to be infected with this virus. The analysis of the SSA data reveals that most of the reported cases from 1994 to 2017 were found in highly industrialized states. This information contradicts the documented relationship between the highest prevalence of infection and the lowest socio-economic status, and supports the necessity of viral detection and notification of HAV cases. Moreover, in spite that four HAV vaccines are available in Mexico and universal vaccination has been shown to be beneficial in developing countries in terms of declining endemicity, HAV vaccination is not mandatory in Mexico. In this review, preventive strategies including appropriate diagnosis, vaccination and public health policies on the basis of the epidemiologic status of HAV in Mexico are discussed., (Copyright © 2019 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

The glycinocins are a class of calcium-dependent, acidic cyclolipopeptide antibiotics structurally related to the clinically approved daptomycin. Herein, we describe a divergent total synthesis of glycinocins A-C, which differ in the structure of a branched α,β-unsaturated fatty acyl moiety. The three natural products exhibited calcium-dependent antimicrobial activity against Staphylococcus aureus and Bacillus subtilis with MICs ranging from 5.5 to 17 μM.

We recently reported an immune-modulatory role of conjugated bilirubin (CB) in hepatitis A virus (HAV) infection. During this infection the immune response relies on CD4+ T lymphocytes (TLs) and it may be affected by the interaction of HAV with its cellular receptor (HAVCR1/TIM-1) on T cell surface. How CB might affect T cell function during HAV infection remains to be elucidated. Herein, in vitro stimulation of CD4+ TLs from healthy donors with CB resulted in a decrease in the degree of intracellular tyrosine phosphorylation and an increase in the activity of T regulatory cells (Tregs) expressing HAVCR1/TIM-1. A comparison between CD4+ TLs from healthy donors and HAV-infected patients revealed changes in the TCR signaling pathway relative to changes in CB levels. The proportion of CD4+CD25+ TLs increased in patients with low CB serum levels and an increase in the percentage of Tregs expressing HAVCR1/TIM-1 was found in HAV-infected patients relative to controls. A low frequency of 157insMTTTVP insertion in the viral receptor gene HAVCR1/TIM-1 was found in patients and controls. Our data revealed that, during HAV infection, CB differentially regulates CD4+ TLs and Tregs functions by modulating intracellular pathways and by inducing changes in the proportion of Tregs expressing HAVCR1/TIM-1.

Communication between the immune system and metabolic components can be exemplified by the process of heme catabolism. The immunomodulatory functions of the enzymes, substrates and active products related to catabolism of the heme group have been extensively studied. Bilirubin (BR), the final breakdown product of heme, is primarily considered to be a toxic waste product but has recently been considered to be an immunomodulatory metabolite. Through mechanisms that include intracellular signaling and transcriptional control, BR affects those immune cell functions that regulate cell proliferation, differentiation and apoptosis. During the pathogenesis of viral hepatitis, the heme degradation pathway is disrupted, resulting in changes to normal BR concentrations. These alterations have been previously studied mainly as a consequence of the infection. However, little is known about the potential immunomodulatory role played by BR in the development of infectious hepatocellular diseases. Differences in BR levels in the context of viral hepatitis are likely to provide important insights into the metabolite-mediated mechanisms controlling the immune responses underlying both the long-term persistence of hepatitis C virus (HCV) infection and the resolution of hepatitis A virus (HAV) infection during the acute phase. In this review, the cross-talk between heme catabolism and immune function is described in detail. Special emphasis is given to discoveries that hold promise for identifying immunologic features of metabolic products in the resolution of viral diseases.

The mechanisms related to the spontaneous clearance of hepatitis C virus (HCV) have been primarily studied in regions where the infection is endemic. Results of prior studies have been extrapolated to populations with low endemicity, such as Mexico. Herein, we determined the cytokine profiles in serum samples from Mexican patients who spontaneously cleared HCV and patients chronically infected with HCV genotype 1a. Chronic HCV-infected patients displayed increased interleukin (IL)-8 and regulated upon activation, normal T-cell expressed and secreted (CCL-5) secretion, whereas patients who spontaneously cleared HCV showed augmented levels of IL-1 alpha, tumour necrosis factor-alpha, transforming growth factor-beta, monocyte chemoattractant protein-2 (CCL-8), IL-13 and IL-15. Our study suggests that cytokine profiles may predict disease outcome during HCV infection.

We determined the serum IgE levels and T-helper (Th)17-related cytokines during distinct hepatitis A virus (HAV)-induced clinical courses in children. A significantly higher concentration of macrophage inflammatory protein 3α, interleukin (IL)-17E and IL-17F in HAV-infected children with intermediate liver injury compared with those with minor liver damage was found. A reduction in the IgE levels in those patients who showed the highest levels of IL-17F in the group of intermediate liver injury was found. The data suggested that the Th17-related profile is associated with the severity of HAV infection and might play a role on the modulation achieved by HAV during allergies.

Background: Breast cancer treatment leads mutilation and destruction of breast shape, with negative effects on body image and self-esteem., Objectives: Assessment on quality of life after breast reconstruction surgery, impact on sexuality, the cosmetic outcome experienced by the patient, and compare result with patients who refused breast reconstruction., Material and Methods: Retrospective, observational, descriptive, analytic study. We included breast cancer patients treated between April 15 2010 to April 15, 2011. Application of "The Survey Questionnaire short form Health 36" (SF-36) with valid use on Mexican population was conducted to measure quality of life, which uses 8 concepts: physical functioning, physical role, body pain, general health, vitality, social function, emotional role and mental health, the results are transferred to a scale 0 (worst health) to 100 (best health)., Results: 37 patients whit breast reconstruction had the inclusion criteria, mean age was 48.4 years. The score of SF-36 questionnaire in reconstructed patients was 76.8, in control group was 85.19 and mastectomy patients without reconstruction was 72.6. Among the items studied those with the greatest difference was the mental health, emotional role and social function, this means that patients with breast reconstruction are less affected in their social and sexual interaction., Conclusions: The reconstructed patients have a positive impact on quality of life slightly higher, sexuality is significantly worse in patients without breast reconstruction, it is important to inform and offer breast reconstruction because many do not require these procedures for fear or lack of information.

The toxin content in various life cycle stages of tank-cultivated bullseye puffer (Sphoeroides annulatus) were analyzed by mouse bioassay and ESI-MS spectrometry analysis. The presence of toxin content was determined in extracts of sperm, eggs, embryo, larvae, post-larvae, juvenile, pre-adult, and adult fish, as well as in food items used during the cultivation of the species. Our findings show that only the muscle of juveniles, the viscera of pre-adults, and muscle, liver, and gonad of adult specimens were slightly toxic (<1 mouse unit). Thus, cultivated S. annulatus, as occurs with other cultivated puffer fish species, does not represent a food safety risk to consumers. This is the first report of toxin analysis covering the complete life stages of a puffer fish under controlled conditions.

Background: Advances in acute graft-versus-host disease therapy are needed., Design and Methods: We examined the efficacy of sirolimus as primary therapy for acute graft-versus-host disease in 32 patients., Results: Acute graft-versus-host disease involved the skin in 53% of cases, gastrointestinal tract in 66%, liver in 16%. The syndrome was overall grade 1 in 12% cases, grade 2 in 75%, and grade 3 in 13%. Sirolimus was targeted to achieve serum trough levels of 5-14 ng/mL. Sixteen (50%) patients achieved sustained, complete resolution of acute graft-versus-host disease with sirolimus alone. In contrast, 19 of 32 (59%) matched historical controls treated with standard 1 mg/kg steroids achieved complete response (P=0.47). With median follow-up time for surviving patients of 16 (range 6-26) months, one year overall survival was 56% (95% CI 38-74%). The cumulative incidence of relapse at one year was 37% (95% CI 23-60%), and mortality in remission was 20% (95% CI 10-42%). The cumulative incidence of chronic graft-versus-host disease was 55% (95% CI 39-79%). Thrombotic microangiopathy occurred in 3 cases (grade 1 n=1; grade 2 n=2), and responded to dose reduction of calcineurin inhibitor., Conclusions: In this retrospective series, sirolimus demonstrates activity comparable to that of high-dose glucocorticoids in the primary therapy of acute graft-versus-host disease. Confirmation of this activity requires prospective clinical trials.

Severe acute graft-versus-host disease (aGVHD) remains a major source of morbidity and mortality following mismatched unrelated donor hematopoietic cell transplantation (HCT). Through a retrospective analysis, we investigated the efficacy of GVHD prophylaxis with rabbit anti-thymocyte globulin (ATG) 7.5 mg/kg (1 mg/kg given on day -3, then 3.25 mg/kg/day on days -2 and -1 before stem cell infusion) followed by standard tacrolimus plus methotrexate in a consecutive series of 45 HLA partially matched unrelated donor HCT recipients. The cumulative incidence of grade III-IV aGVHD was 11% by 100 days (95% confidence interval [CI] 5%-25%). Moderate to severe chronic GVHD (per NIH consensus criteria) was 19% (95% CI 10%-36%) at 1 year, and 28% (95% CI 16%-48%) at 2 years. With a median follow-up time for surviving patients of 12 months (range: 5-39 months), overall survival was 55% (95% CI 39%-71%) at 1 year, and 45% (95% CI 27%-63%) at 2 years. Nonrelapse mortality was 11% (95% CI 5%-25%) by 100 days post-HCT, 26% (95% CI 16%-44%) by 1 year, and 30% (95% CI 18%-50%) by 2 years. The cumulative incidence of primary disease relapse was 23% (95% CI 13%-41%) at 1 year, and 33% (95% CI 20%-56%) by 2 years after HCT. Cytomegalovirus (CMV) infection or reactivation varied according to recipient and donor CMV serostatus. Epstein-Barr Virus (EBV) reactivation occurred in 54% (95% CI 40%-71%) of patients. Preemptive rituximab therapy was administered for EBV reactivation, however, posttransplant lymphoproliferative disorder was diagnosed in 5 (11%) cases, and was fatal in 1. A regimen of ATG 7.5 mg/kg total ending on day -1 effectively decreased the occurrence of grade III-IV aGVHD and severe chronic GVHD., (Copyright © 2011 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Differential A-fibre block of human peripheral nerves changes the sensation evoked by innocuous cooling (approximately 24 degrees C) of the skin from 'cold' to 'hot' or 'burning', and this has been attributed to activity in unidentified unmyelinated fibres that is normally masked or inhibited by activity in Adelta cold fibres. Application of the TRPM8 agonist menthol to the skin evokes 'burning/stinging' as well as 'cold', and the unpleasant sensations are also enhanced by A-fibre block. In this study we used microneurography to search for C fibres in human skin activated by cooling and menthol, which could be responsible for these phenomena. Afferent C fibres were classified by activity-dependent slowing as Type 1A (polymodal nociceptor), Type 1B (mechanically insensitive nociceptor) or Type 2 (cold sensitive), and their responses to heating and cooling ramps were measured before and after topical application of menthol preparations (2-50%). The only C fibres activated by menthol were the Type 2 fibres, which discharged vigorously with innocuous cooling and were strongly activated and sensitized to cooling by menthol. Unlike an Adelta cold fibre, they continued to discharge at skin temperatures down to 0 degrees C, and most (13/15) were also activated by heating. We propose that the Type 2 C fibres, although resembling Adelta cold fibres in their responses to innocuous cooling and menthol, have a more complex sensory function, colouring with a 'hot-burning' quality the perceptions of low and high temperatures. Their bimodal thermoreceptive properties may help account for several puzzling psychophysical phenomena, such as 'innocuous cold nociception', 'paradoxical heat' and the thermal grill illusion, and also for some neuropathic pains.

Introduction: Rheumatoid arthritis is an autoimmune inflammatory disease of unknown etiology, free radicals have been implicated in the genesis and perpetuation of damage in this pathology., Objective: To evaluate the anti-inflammatory effect of Cu,Zn-superoxide dismutase (SOD) obtained from two different sources (bovine erythrocytes, Be-SOD, and Debaryomyces hansenii, Dh-SOD) with Type II Collagen-induced Arthritis model in rats., Material and Methods: Arthritis was induced by repeated injection of a porcine type II collagen-incomplete Freund adjuvant suspension on the back of Dark Augui (DA) rats. Arthritis was clinically evaluated throughout the study. Body weight was determined at three different times. Two different doses for each treatment (Be-SOD, Dh-SOD) were tested: 100 and 1,000 U/kg. At the end of the trial (day 28), histological analyses of the most inflamed ankle joint, as well as serum anti-collagen antibodies, were determined., Results: Both sources of SOD decreased, although to a different extent, the incidence and severity of the disease. Arthritis score was lower in all treatments, except for the low dose of Be-SOD. Groups receiving either source of SOD showed a significant weight increase compared to the placebo group. Histological damage was similar in all groups. Only the group that received the highest dose of Dh-SOD showed a significant lower antibody titer; nevertheless, no correlation appears to derive from arthritis score and antibody titer., Conclusion: Our findings suggest that, although unable to counteract the arthritis syndrome, SOD may still be beneficial due to its anti-inflammatory activity. In the case of Dh-SOD, the best effect was observed at the highest dose tested.

Postharvest rotting caused by Penicillium italicum Wermer is responsible for significant economic losses of orange (Citrus sinensis (L.) Osbeck) and lemon (C. limon Burm. f.) worldwide, but until now was not described on lemons (C. aurantifolia (Chistm.) Swingle) in Mexico. During May 2002, we analyzed 400 fruits of lemon collected in the state of Colima, which is the most important lemon producer in Mexico. Rotting and softened areas covered with a white mycelium and blue conidia were observed on approximately 30% of the fruits. Affected tissue was plated onto potato dextrose agar (PDA) for fungal isolation and identification. Following the morphological criteria (1) and the internal transcribed spacer 1 (ITS1), 5.8S, and ITS2 region of the ribosomal DNA (2) (GenBank Accession No. DQ991463), the fungus was identified as P. italicum and deposited in the Colección Microbiana y de Cultivos Celulares CINVESTAV-IPN, México. For the pathogenicity test, the fungus was grown on PDA for 1 week. Four drops (15 μl each) of a sterile water suspension of 10 6 conidia per ml were placed in four wounds of 3 × 3 × 3 mm produced with a scalpel on the fruit surface. Five plastic boxes with six fruits each were placed in an environmental chamber at 12°C and 90% relative humidity. After 10 days, all fruit rotted in a similar way as naturally infected fruit on trees. Control fruits inoculated with sterile distilled water were symptomless. The test was repeated and the results were similar, confirming Koch's postulates. To our knowledge, this is the first report describing the isolation and pathogenicity of P. italicum on lemon (C. aurantifolia) in Colima, Mexico, which may have important implications in fruit quality and storage. References: (1) Z. Kozakieweicz. IMI Descriptions of Fungi and Bacteria. 155, Sheet 1548, 2002. (2) M. J. Pianzzola et al. Plant. Dis. 88:23, 2004.

Five patients with small-fibre neuropathy characterized by temperature-dependent spontaneous pain, hyperalgesia/allodynia and signs of neurogenic inflammation were studied clinically and thermographically, and by microneurography. Thermography revealed hyperthermia confined to painful and hyperalgesic skin of distal extremities, in absence of sympathetic vasomotor denervation. Quantitative sensory testing documented either reduced thresholds or increased suprathreshold magnitude for heat pain. Microneurography identified 13 primary cutaneous C-nociceptors generating abnormal impulses in response to electrical stimuli and, in one patient, nociceptors firing spontaneously. All five patients showed examples of double spikes, in which a single brief electrical stimulus occasionally or regularly evoked two impulses. In one case, a second impulse occurred at one of three different delays. In all five patients, warming of the skin increased the probability of a second impulse occurring. Impulse doubling has previously been reported as occurring rarely in normal subjects and is attributable to unfiltering of multiple orthodromic impulses due to unidirectional conduction failure at branch points. A higher incidence of double firing in neuropathic pain patients is probably due to a reduced safety factor for conduction in the terminal arborizations of their C-nociceptors. These observations show that unidirectional conduction block provides a peripheral mechanism of temperature-dependent nociceptor hyperactivity in small-fibre neuropathy that may contribute to hyperalgesia.

The sensory territories of different cutaneous fascicles of the superficial radial nerve were delineated by microneurography at the level of the distal forearm in humans. Three fascicular patterns were found at this level: one supplying the dorsum of the radial aspect of the dorsum of the hand over the first dorsal interosseous space; another supplying the lateral aspect of the first metacarpal extending to the lateral aspect of the thumb; and a third innervating the second interosseous space and the proximal phalanx of the index and middle fingers. The compound fascicular territory is comparable to the classical territory described for the superficial radial nerve. Intraneural microstimulation of individual fascicles did not evoke paraesthesiae or pain beyond their fascicular territory, regardless of the stimulus intensity. We conclude that the superficial radial nerve at the forearm in man is composed of only three fascicles, as shown by the present study and from previous anatomical work. Referred pain seems related to nerve activity in afferent fibres from fascicles supplying deep tissues and muscles, not from cutaneous afferents.

A dinoflagellate bloom ("red tide" event) dominated by the toxic Gymnodinium catenatum Graham (Gymnodiniales, Dinophyceae; 99.7%) and the noxious Noctiluca scintillans (Mcartney) Kofoid (Noctilucaceae, Dinophyceae; 0.3%) was observed in Bahia de Mazatlán Bay, México, on 24-26 January 2000. Photographic and microscopic analysis of samples during such an event, allowed us to collect evidence of a marked The particularity of grazing of G. catrenatum by by N. scintillans cells, suggesting a mechanism of "biocontrol" between these species that may contribute to attenuate a potentially toxic phenomenon under natural conditions.

An event characterized by sudden increase in phytoplankton population, in the sea or aqueous environment, is often designated by different Spanish terms that attempt to describe the nature, aspect, characteristics, and/or properties of such phenomena. In this communication, we discuss the convenience of reaching an agreement among the Spanish-speaking scientific community to use a simple Spanish term that could be much more informative and accurate when referring to Harmful Algal Blooms (HABs), in general. Summarizing the different Spanish terms historically employed to describe the proliferation of noxious phytoplankton in the sea, we propose "Proliferación Microalgal Nociva" (PMN = HAB) as a term that, on the basis of its etymological meaning could be considered correct. Its use could help to avoid the prevailing confusion in our language caused by different misleading terms now employed when referring to a Harmful Algal Bloom event.

1. Microneurography was used to search for primary afferents responsive to innocuous low temperature in human nerves supplying the hairy skin of the hand or foot. Eighteen units were identified as cold-specific units: they displayed a steady-state discharge at skin temperatures in the range 28-30 degrees C, they were sensitive to small changes in temperature, and they responded vigorously when a cool metal probe touched their receptive fields (RFs). They were insensitive to mechanical stimuli and sympathetic activation. Their RFs comprised one, or at most two, spots less than 5 mm in diameter. 2. Nine units were characterised in detail by a series of 10 s cooling and warming pulses from a holding temperature of 35 degrees C. The threshold temperature for activation by cooling was 29.4 +/- 2.0 degrees C (mean +/- S.D.). Adaptation of the responses to supra-threshold cooling pulses was partial: mean peak and plateau firing rates were maximal on steps to 15 degrees C (35.9 and 19.9 impulses x s(-1), respectively). Three of these units also displayed a paradoxical response to warming, with a mean threshold of 42.3 degrees C. 3. Sixteen of the eighteen cold-specific units were also studied by electrical stimulation of their RFs. They conducted in the velocity range 0.8-3.0 m x s(-1). When stimulated at 2 Hz, their latency increased according to a characteristic time course, reaching a plateau within 3 min (mean slowing (+/- S.D.) 5.2 +/- 1.1 %) and recovering quickly (50 % recovery in 17.8 +/- 4.5 s). 4. To reconcile these findings with previous studies of reaction times and the effects of nerve compression on sensation, it is concluded that either human cold-specific afferent fibres are incompletely myelinated 'BC' fibres, or else there are C as well as A(delta) cold fibres, with the C fibre group contributing little to sensation.

A pool of heparan sulphate-binding proteins (HSBPs) from Helicobacter pylori culture supernates was obtained by sequential ammonium sulphate precipitation and affinity chromatography on heparin-Sepharose. The chromatographic procedure yielded one major fraction that contained proteins with heparan sulphate affinity as revealed by inhibition studies of heparan sulphate binding to H. pylori cells. Preparative iso-electric focusing, SDS-PAGE and blotting experiments, with peroxidase(POD)-labelled heparan sulphate as a probe, indicated the presence of two major extracellular proteins with POD-heparan sulphate affinity. One protein had a molecular mass of 66.2 kDa and a pI of 5.4, whilst the second protein had a molecular mass of 71.5 kDa and a pI of 5.0. The N-terminal amino acid sequence of the 71.5-kDa HSBP did not show homology to any other heparin-binding protein, nor to known proteins of H. pylori, whereas the 66.2-kDa HSBP showed a high homology to an Escherichia coli chaperon protein and equine haemoglobin. A third HSBP was isolated from an outer-membrane protein (OMP) fraction of H. pylori cells with a molecular mass of 47.2 kDa. The amino acid sequence of an internal peptide of the OMP-HSBP did not show homology to the extracellular HSBP of H. pylori, or to another microbial HSBP.

Objectives: To gain understanding of the mechanism and meaning of improvement of hypoaesthesia after a diagnostic intervention, and of the nature of the population that displays such a sign., Methods: Patients with chronic "neuropathic" pain underwent rigorous clinical and laboratory investigations, including placebo controlled local anaesthetic block. Patients displaying profound regional cutaneous hypoaesthesia and pain entered the study through either of two criteria: (a) reversal of hypoaesthesia after diagnostic block, (b) nerve injury as the cause of hypoaesthesia and pain. The semeiology displayed by these patients together with the behaviour of their sensory phenomena in response to blocks were compared. Three groups were expected: (1) patients with "neuropathic" pain with profound hypoaesthesia reversed by block, but without neuropathy; (2) patients whose hypoaesthesia did not reverse and who had neuropathy as the cause of their sensory dysfunction; and (3) patients whose hypoaesthesia reversed, and had neuropathy., Results: Two groups emerged: (1) patients with profound hypoaesthesia reversed by block, but without neuropathy (27 patients), and (2) patients whose hypoaesthesia did not reverse and who had a neuropathy (13 patients). No patient with neuropathy was found whose cutaneous hypoaesthesia improved with block. The first group displayed the sensory-motor characteristics of psychogenic pseudoneuropathy. The semeiology of the second group was in keeping with organic neuropathy and displayed no pseudoneurological features. Spontaneous pain was relieved by placebo in 66.6% of the patients in groupl and 53.8% in group 2., Conclusions: Such reversal of hypoaesthesia is due to a placebo effect, acting on a psychogenic symptom because: (a) 27 of 27 patients in which the sign occurred had absence of nerve disease behind the "neuropathic" symptoms, (b) In 26 of 27 patients the area of hypoaesthesia was non-anatomical, (c) 16 of 27 patients had other sensory-motor signs that could not be explained as a result of organic pathology (give way weakness and punctual denial of hypoaesthesia), and (d) the phenomenon was not found in patients with organic neuropathy.

1. Fifty-five C-polymodal nociceptors innervating hairy skin in human volunteers were tested for discrete stimulus-response properties through microneurography. 2. All fifty-five units were responsive to mechanical and heat stimuli. Twenty-two (40%) of these exhibited an additional response to noxious low temperature. The twenty-two mechano-heat-cold nociceptors displayed similar receptor responses to heat and mechanical stimuli, and conduction velocity, as those of the pure mechano-heat C-polymodal nociceptors. 3. Low temperature stimuli between 19 and 0 degree C evoked responses at low discharge frequency (0.4 +/- 0.22 impulses s-1, mean +/- S.E.M.) in the twenty-two units sensitive to such energy. These units displayed a tendency to decrease their discharge after a few seconds of steady stimulation. 4. Three units tested with a freezing stimulus responded with relatively vigorous discharge, which never exceeded the maximal discharge frequency elicited by either mechanical or heat stimuli. One of these units became sensitized to heat after the freezing challenge. 5. It is concluded that a subpopulation of C-polymodal nociceptors is sensitive to noxious low temperature and may thus contribute to the determination of cold pain. The same type of primary afferent is probably one mediator of the symptom cold hyperalgesia in peripheral nerve disease.

The sympathetic vasomotor innervation of the skin of the human hand was studied in 47 subjects who underwent local anaesthetic block of ulnar, median or radial nerves at elbow or wrist levels. Areas of cutaneous anaesthesia were compared with cutaneous territories of paralytic vasodilatation delineated by infrared telethermography. It was found that: (1) during ulnar nerve block the area of vasodilatation matched the area of anaesthesia in all 15 cases; (2) median nerve block induced paralytic vasodilatation which, in 14 of 15 cases, matched the area of cutaneous anaesthesia in median territory, but also extended to the unanaesthetised lateral part of the dorsum of the hand; (3) no vasodilatation developed during radial nerve block in 17 of 18 cases, whereas areas of sympathetic sudomotor paralysis matched the area of radial sensory loss in all 5 subjects in whom sweating function was studied. It is concluded that: (1) the ulnar nerve supplies vasomotor fibres to its cutaneous sensory territory, no less and no more; (2) the median nerve normally provides supplementary vasomotor innervation to the skin of the radial aspect of the dorsum of the hand; (3) the radial nerve supplies sudomotor innervation for the lateral aspect of the dorsum of the hand, but (4) does not normally contribute vasomotor sympathetic fibres to the skin of the hand.

1. Effects of rate of rise of temperature stimuli applied to skin on (i) unitary receptor threshold and frequency response often single C nociceptors, and (ii) on magnitude and reaction times of evoked pain were studied in fifteen healthy human volunteers. 2. Temperature ramps of 32 to 45 or 47 degrees C were applied at three consistent rates of rise to receptive fields of C nociceptors in dorsum of foot (n = 9) or hand (n = 1). For rates of rise of 0.3, 2.0 and 6.0 degrees C/s, mean receptor threshold for heat was remarkably uniform: 41.5 +/- 0.57, 41.5 +/- 0.61 and 41.9 +/- 0.71 degrees C respectively. 3. The mean discharge rate of the ten cutaneous C nociceptors increased with rate of rise of temperature stimuli: 1.22 +/- 0.13, 4.57 +/- 0.49 and 13.45 +/- 0.71 impulses/s, respectively, for stimulus temperature rates of 0.3, 2.0 and 6.0 degrees C/s. 4. Magnitude estimates of pain for thirteen subjects also increased with rate of rise of temperature stimuli. Mean normalized magnitude estimates of heat pain were: 11.8 +/- 1.55, 15.1 +/- 0.84 and 28.0 +/- 1.87 for stimulus rates of rise of 0.3, 2.0 and 6.0 degrees C/s, respectively. 5. Results of simultaneous recordings of reaction time for pain and of C nociceptor responses to heat ramps given at 2.0 degrees C/s, in three subjects, indicate that under those circumstances heat pain messages are exclusively mediated by C nociceptors.

A new method of eliciting experimental pain in man is described. Microelectrodes are inserted percutaneously into the peripheral nerves of awake subjects, and are positioned close to nociceptive fibres in order to elicit pain during intraneural electrical stimulation. Under fixed stimulation conditions the estimated magnitude of evoked pain remains relatively stable, unless a high stimulus frequency is used, which may lead to excitation failure of nociceptive fibres. This method can be employed to test for possible central modulation of pain, for instance by analgesic agents, since peripheral receptors are bypassed.

While undergoing long-term physiotherapy, a 41 year old woman with a chronic S1 radiculopathy developed progressive, painless enlargement of the weak calf. Gastrocnemius muscle biopsy disclosed changes of partial denervation and reinnervation, with small groups of type I and type II atrophic muscle fibres and abundant hypertrophic fibres of both types but mostly type II. It is postulated that, in addition to comprensatory work-induced type II muscle fibre hypertrophy, there was an element of (type I) stretched-induced hypertrophy of denervated fibres, a condition well recognised experimentally but not documented in man.