Novel germline variants of CDKN1B and CDKN2C identified during screening for familial primary hyperparathyroidism.

PURPOSE: CDKN1B mutations were established as a cause of multiple endocrine neoplasia 4 (MEN4) syndrome in patients with MEN1 phenotype without a mutation in the MEN1 gene. In addition, variants in other cyclin-dependent kinase inhibitors (CDKIs) were found in some MEN1-like cases without the MEN1 mutation. We aimed to describe novel germline mutations of these genes in patients with primary hyperparathyroidism (PHPT). METHODS: During genetic screening for familial hyperparathyroidism, three novel CDKIs germline mutations in three unrelated cases between January 2019 and November 2021 were identified. In this report, we describe clinical features, DNA sequence analysis, and familial segregation studies based on these patients and their relatives. Genome-wide DNA study of loss of heterozygosity (LOH), copy number variation (CNV), and p27/kip immunohistochemistry was performed on tumour samples. RESULTS: DNA screening was performed for atypical parathyroid adenomas in cases 1 and 2 and for cystic parathyroid adenoma and young age at diagnosis of PHPT in case 3. Genetic analysis identified likely pathogenic variants of CDKN1B in cases 1 and 2 and a variant of the uncertain significance of CDKN2C, with uniparental disomy in the tumour sample, in case 3. Neoplasm screening of probands showed other non-endocrine tumours in case 1 (colon adenoma with dysplasia and atypical lipomas) and case 2 (aberrant T-cell population) and a non-functional pituitary adenoma in case 3. CONCLUSION: Germline mutations in CDKIs should be included in gene panels for genetic testing of primary hyperparathyroidism. New germline variants here described can be added to the current knowledge.

Therapeutic management of peritonitis: a comprehensive guide for intensivists.

PURPOSE: The management of peritonitis in critically ill patients is becoming increasingly complex due to their changing characteristics and the growing prevalence of multidrug-resistant (MDR) bacteria. METHODS: A multidisciplinary panel summarizes the latest advances in the therapeutic management of these critically ill patients. RESULTS: Appendicitis, cholecystitis and bowel perforation represent the majority of all community-acquired infections, while most cases of healthcare-associated infections occur following suture leaks and/or bowel perforation. The micro-organisms involved include a spectrum of Gram-positive and Gram-negative bacteria, as well as anaerobes and fungi. Healthcare-associated infections are associated with an increased likelihood of MDR pathogens. The key elements for success are early and optimal source control and adequate surgery and appropriate antibiotic therapy. Drainage, debridement, abdominal cleansing, irrigation, and control of the source of contamination are the major steps to ensure source control. In life-threatening situations, a "damage control" approach is the safest way to gain time and achieve stability. The initial empirical antiinfective therapy should be prescribed rapidly and must target all of the micro-organisms likely to be involved, including MDR bacteria and fungi, on the basis of the suspected risk factors. Dosage adjustment needs to be based on pharmacokinetic parameters. Supportive care includes pain management, optimization of ventilation, haemodynamic and fluid monitoring, improvement of renal function, nutrition and anticoagulation. CONCLUSIONS: The majority of patients with peritonitis develop complications, including worsening of pre-existing organ dysfunction, surgical complications and healthcare-associated infections. The probability of postoperative complications must be taken into account in the decision-making process prior to surgery.

Infección intraabdominal y tratamiento antibiótico / No disponible

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Recomendaciones en el tratamiento antibiótico empírico de la infección intraabdominal / No disponible

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Recomendaciones en el tratamientoantibiótico empírico de la infecciónintraabdominal / Recommendations in the empiric anti-infective agents of intra-abdominal infection

Un número importante de pacientes con infección intraabdominaldesarrollan estados avanzados de la infeccióny la mortalidad es todavía superior al 20%. El fracaso esmultifactorial y se relaciona con el incremento de resistenciasbacterianas, el tratamiento empírico inapropiado, la mayorcomorbilidad de los pacientes y el mal control del foco de infección.Estas guías analizan cada uno de estos problemas yproponen medidas para evitar el fracaso, basadas en la mejorevidencia científica actual (AU)

A significant number of patients with abdominal infectiondevelop advanced stages of infection and mortalityis still above 20%. Failure is multifactorial and isassociated with an increase of bacterial resitance, inappropriateempirical treatment, a higher comorbidity of patientsand poor source control of infection. These guidelinesdiscuss each of these problems and propose measuresto avoid the failure based on the best current scientificevidence (AU)

[Recommendations in the empiric anti-infective agents of intra-abdominal infection]. / Recomendaciones en el tratamiento antibiótico empírico de la infección intraabdominal.

A significant number of patients with abdominal infection develop advanced stages of infection and mortality is still above 20%. Failure is multifactorial and is associated with an increase of bacterial resistance, inappropriate empirical treatment, a higher comorbidity of patients and poor source control of infection. These guidelines discuss each of these problems and propose measures to avoid the failure based on the best current scientific evidence.

Guía de tratamiento de la infección producida por Staphylococcus aureus resistente a meticilina / Guidelines for the treatment on infections caused by methicillin-resistant Staphylococcus aureus

Las infecciones por Staphylococcus aureus resistente a meticilina (SARM) han experimentado importantes cambios en los últimos 5 años que condicionan la elección del tratamiento antibiótico: a) incremento de su frecuencia en el hospital y aparición de cepas de SARM adquiridas en la comunidad, sin ninguna relación con las de origen nosocomial y con un comportamiento clínico en cierto modo peculiar; b) progreso en la comprensión de los parámetros de farmacocinética/farmacodinamia (FC/FD) que rigen la eficacia de los antimicrobianos, incluyendo el reconocimiento de la importancia que tiene el valor de la concentración mínima inhibitoria (CMI) de vancomicina en el pronóstico de la infección por SARM tratada con glucopéptidos; c) la implementación en los laboratorios de microbiología de técnicas para la identificación rápida de SARM en muestras clínicas; d) clara evidencia de la pérdida de eficacia de vancomicina frente a SARM cuando la CMI es > 1 mg/ml, y e) la introducción en terapéutica de nuevos antibióticos activos frente a SARM (linezolid, daptomicina, tigeciclina). Ante esta situación, el desarrollo de guías de tratamiento para las infecciones habituales por SARM parece ser necesario para mejorar la eficacia y reducir la mortalidad (AU)

Infections due to methicillin-resistant Staphylococcus aureus (MRSA) have undergone important changes in the last five years that have influenced the choice of therapy: i) increase of their frequency in hospital-associated settings and, more recently, in community settings; ii) better knowledge of clinical implications of the pharmacokinetic and pharmacodynamic properties of vancomycin; iii) improvement of current standard methods for rapid detection of MRSA in clinical samples; iv) clear evidence that vancomycin is losing efficacy against MRSA with MIC > 1 μg/mL; and v) appearance of new antibiotics suitable for use in these infections (linezolid, daptomycin, tigecyclin). Under this situation guidelines for the treatment of common infections caused by MRSA appear to be necessary to improve the efficacy and reduce the mortality (AU)

[Guidelines for the treatment on infections caused by methicillin-resistant Staphylococcus aureus]. / Guía de tratamiento de la infección producida por Staphylococcus aureus resistente a meticilina.

Infections due to methicillin-resistant Staphylococcus aureus (MRSA) have undergone important changes in the last five years that have influenced the choice of therapy: i) increase of their frequency in hospital-associated settings and, more recently, in community settings; ii) better knowledge of clinical implications of the pharmacokinetic and pharmacodynamic properties of vancomycin; iii) improvement of current standard methods for rapid detection of MRSA in clinical samples; iv) clear evidence that vancomycin is losing efficacy against MRSA with MIC > 1 microg/mL; and v) appearance of new antibiotics suitable for use in these infections (linezolid, daptomycin, tigecyclin). Under this situation guidelines for the treatment of common infections caused by MRSA appear to be necessary to improve the efficacy and reduce the mortality.

Cancer cachexia: a therapeutic approach.

Cancer cachexia is a complex syndrome which occurs in more than two-thirds of patients who die with advanced cancer. The main components of this pathological state are anorexia and metabolic abnormalities such as glucose intolerance, fat depletion, and muscle protein catabolism among others. The aim of the present study is to review the different therapeutic approaches that have been designed to fight and counteract cancer cachexia.

[Prospective randomized trial of meropenem versus cefotaxime and metronidazole in the treatment of intraabdominal infections]. / Comparación prospectiva, aleatoria y abierta de meropenem frente a cefotaxima y metronidazol en el tratamiento de las infecciones intraabdominales.

BACKGROUND: The empiric antibiotic treatment of intraabdominal infections is in constant evolution. Monotherapy appears to be a desirable goal because of the simplicity of its administration, lack of toxic effects and wide spectrum. PATIENTS AND METHODS: A multicentre, prospective, randomized, open study was carried out to compare two antibiotic regimens in the treatment of intraabdominal infections in patients undergoing surgery. Ninety-eight consecutive patients were randomly allocated into two groups. One group (GM, n = 51) received meropenem (1 g/8 h) and the other (GCM, n = 47) a combination of cefotaxime (2 g/8 h) plus metronidazol (0.5 g/8 h). Clinical and bacteriological responses were assessed at the end of treatment and at 2-4 weeks. RESULTS: The severity of patients as assessed by the APACHE II score was similar in both groups (GM: 7.2 and GCM: 8.1). Three patients in each group could not be evaluated due to premature interruption of treatment or deviation from the protocol. The mean duration of treatment was 7.4 days in GM and 7.9 days in GCM. A satisfactory clinical response was obtained in 95% of patients in both groups. 31 patients (61%) in GM and 26 patients (55%) in GCM were bacteriologically evaluable. Bacteriological erradication was achieved in 94% of patients in GM and in 92% of patients in GCM. CONCLUSION: Meropenem is a good alternative for single antibiotic therapy in intraabdominal infections of moderate severity.

Interleukin-6 gene-deficient mice show impaired defense against pneumococcal pneumonia.

Induction of pneumonia in C57Bl/6 mice by intranasal inoculation with 10(6) cfu of Streptococcus pneumoniae resulted in sustained expression of interleukin (IL)-6 mRNA in lungs and increases in lung and plasma IL-6 concentrations. In IL-6-deficient (IL-6-/-) mice, pneumonia was associated with higher lung levels of the proinflammatory cytokines tumor necrosis factor-alpha, IL-1beta, and interferon-gamma and of the antiinflammatory cytokine IL-10 than in wild type (IL-6+/+) mice (all P < .05). Also, the plasma concentrations of soluble tumor necrosis factor receptors were higher in IL-6-/- mice (P < .05), while the acute-phase protein response was strongly attenuated (P < .01). Lungs harvested from IL-6-/- mice 40 h after inoculation contained more S. pneumoniae colonies (P < .05). IL-6-/- mice died significantly earlier from pneumococcal pneumonia than did IL-6+/+ mice (P < .05). During pneumococcal pneumonia, IL-6 down-regulates the activation of the cytokine network in the lung and contributes to host defense.

Response of severely malnourished patients to preoperative parenteral nutrition: a randomized clinical trial of water and sodium restriction.

Preoperative parenteral nutrition (PPN) may be beneficial for severely malnourished patients who are candidates for a major elective surgical procedure. The response to PPN, however, has not been thoroughly investigated. Expansion of the extracellular water compartment may occur in some patients, producing a further decrease in the serum albumin concentration and increasing the postoperative complications. Our aims were to investigate the occurrence of and factors associated with water and sodium retention during PPN and its impact on postoperative respiratory complications. Forty-one patients with gastrointestinal cancer and severe malnutrition (weight loss > 15% and/or serum albumin < 35 g/L) were randomly allocated to two groups receiving isocaloric isonitrogenous PPN for 10 d. The Standard PPN Group (SG, n = 19) received 70% of nonprotein calories as glucose, 45 cc of water.kg-1.d-1, and 140 mEq/d of sodium chloride; and the Modified Group (MG, n = 22) received 70% of calories as fat, 30 cc of water.kg-1.d-1, and no sodium. Weight and albumin changes, diuresis, sodium and water balances, and postoperative complications were recorded. At the end of PPN, the SG showed a higher weight gain (0.8 versus -1.5 kg, P = 0.0001) and albumin decrease (-0.7 versus 2.3 g/L, P = 0.006). Diuresis and sodium balance were greater in the SG (1,230 versus 959 mL/d, P = 0.003 and 40 versus -27 mEq/d, P = 0.001). Weight changes correlated with water (r2 = 0.46, P = 0.001) and sodium (r2 = 0.62, P = 0.0001) balances. Inappropriate responses to PPN in both groups (expansion or depletion of the extracellular water compartment) were associated with a significant increase in pulmonary postoperative complications. During PPN, extracellular water expansion--as determined by increasing weight and lowering of the serum albumin concentration--and aggressive fluid therapy to treat water and sodium depletion seem crucial to the development of postoperative respiratory complications.

Catecholamines increase monocyte TNF receptors and inhibit TNF through beta 2-adrenoreceptor activation.

Postinjury deficits in monocyte tumor necrosis factor receptors (moTNFR) activity may alter beneficial functions during an inflammatory response. Several counter-regulatory hormones elicited during inflammation may modulate tumor necrosis factor (TNF) activity, but little is known about their influence on moTNFR. Also, catecholamines inhibit TNF production, but the adrenoreceptor mechanism of this effect has not been fully clarified. To determine the effect of catecholamines and corticosteroids on moTNFR, whole blood was coincubated for up to 8 (moTNFR) or 24 h (cytokines) in the presence of lipopolysaccharide (100 ng/ml) and 1) epinephrine (Epi, 10(-6) M), dexamethasone (Dex, 10(-6) M) or both (EpiDex, 10(-6) M) to assess the expression of total moTNFR, moTNFR-I, and moTNFR-II. 2) Epi and norepinephrine (EpiNE, 10(-6) M) and the alpha 1 + 2-, beta 1 + 2-, beta 1-, or beta 2-adrenergic antagonists were used to assess the role of such adrenoreceptors on total moTNFR and TNF production, and N6,2'-O-dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP) alone or in combination with the phosphodiesterase inhibitor Ro-20-1724/000, to study the cAMP-dependent pathway on total moTNFR. We found that Epi upregulated total moTNFR and moTNFR-II. Dex did not significantly influence total moTNFR or moTNFR-II. Also, EpiNE increased total moTNFR and inhibited TNF by a beta 2-dependent mechanism. DBcAMP (10(-5) M) modestly enhanced total moTNFR. This suggests a common mechanism for acutely enhancing moTNFR and attenuation of soluble TNF appearance during conditions of severe stress.

Biologic control of injury and inflammation: much more than too little or too late.

A generalized host inflammatory response is necessary to orchestrate the maintenance or recovery of tissue repair and immune competence following severe injury or infection. When excessive in initial magnitude or duration, however, these otherwise beneficial inflammatory processes may eventuate in deterioration rather than restoration of homeostasis. Although the adverse consequences of excessive inflammatory stimuli may be acutely evident, their influences are more often insidious. A complex cascade of endogenously derived proinflammatory mediators are currently hypothesized to be responsible for both the beneficial and the adverse sequelae of infection and injury. The cytokine proteins tumor necrosis factor and interleukin 1 have been most widely studied as potential targets for antagonist intervention in both experimental models and prospective clinical trials. Preclinical evidence supporting these approaches is briefly discussed herein, as are the results of clinical trials attempting to modulate cytokine influences in the presence of sepsis. The present discussion focuses on potential insights gained from these investigations and the evolving appreciation for the importance of cytokine counterregulatory mechanisms. Examples of potentially complex interactions between inflammatory cytokines and infection-induced antagonist proteins or counterregulatory hormones are provided. It is hypothesized that a sustained imbalance among these proinflammatory and counterregulatory influences may be a critical determinant of outcome in patients with severe infection.

A new model of intraabdominal abscess: usefulness for hydrosaline metabolism studies in parenteral nutrition associated with sepsis.

The present study was set up to develop a new model of intraabdominal abscess (IAA) useful for hydrosaline metabolism studies based on the ligation of the appendix (AL) and wrapping of the appendix tip with omentum. Two experiments were designed: (1) to characterize the model and (2) to investigate extracellular volume (ECV) changes during parenteral nutrition (PN). Four groups of rabbits were studied at 3 (3DA) and 7 days (7DA) after AL or sham operation. PN was given for 6 days to two groups of septic rabbits: high volume HV) and low volume (LV) groups received 100 and 70 ml/kg.day of water with 7 and 0 meq/day of ClNa, respectively. Serum albumin (SA), ECV, and weight, water and sodium balances were determined. In 3DA, weight loss, reduced spontaneous intake, negative water balance, and reduction in SA were noted. Low SA, higher weight loss, and reduced intake were still observed in 7DA. SA correlated with ECV (r2 = 0.61, P = 0.003) in 7DA. Positive nitrogen balance was achieved during PN. The HV group had higher water and sodium balances than LV. In the HV group only, SA negatively correlated with sodium balance and with ECV at the end of PN (r2 = 0.87, P = 0.0007 and r2 = 0.9, P = 0.0001). The impact on hydrosaline metabolism of IAA in this model resembles that of moderate sepsis in humans. SA decrease appears to have two major components: escape around the inflammatory area and dilution. ECV expansion after PN is influenced by the initial SA concentration.

Extracellular volume, nutritional status, and refeeding changes.

ECW, and particularly its interstitial component, expands easily with malnutrition, sepsis, and trauma and after aggressive intravenous fluid therapy. In this scenario, hypoalbuminemia is usually the result of both an increased capillary escape rate due to leaky endothelium and increased distribution volume; this can be worsened by artificial intravenous nutrition with sodium, water, and glucose. Monitoring ECW is essential during TPN. Short-term changes in weight and serum albumin concentration are helpful to control ECW volume and prevent ECW expansion. Tetrapolar bioimpedance analysis is a promising technique for accurate bedside measurement of changes in body fluid compartments.

Influence of calorie source on the physiological response to parenteral nutrition in malnourished rabbits.

The present study was designed to investigate whether calorie source influences sodium and water metabolism and sympathetic activity during parenteral nutrition (PN). 20 New Zealand rabbits were starved until a mean weight loss of 18% was achieved and then re-fed for 6 days with 2 formulae of PN with different glucose-fat proportions. In the Glucose group (n = 9), 70% of non-protein calories were given as glucose while in the Lipid group (n = 11), 70% of non-protein calories were administered as lipids. Rabbits with a high glucose intake showed significantly higher weight gain (151 +/- 87 vs. 52 +/- 7 g, P = 0.01), water cumulative balance (542 +/- 132 vs. 411 +/- 87 ml; P = 0.02) and urinary metanephrine excretion (0.42 +/- 0.12 vs. 0.30 +/- 0.1 mumol/d, P = .03). Only in this group, urinary metanephrines correlated positively with water and sodium balances (r2 = 0.6; P = 0.02 and r2 = 0.7; P = 0.009 respectively). The Glucose group showed 2 different responses and in a second experiment 10 additional rabbits were added to this group to allow a statistical analysis of the response pattern: half of the animals increased their extracellular water (ECW) compartment while the remaining animals did not. The former group had higher sodium balance (13.9 +/- 8 vs. 4.3 +/- 5; P = 0.004) and wet lung weight (8.9 +/- 0.9 vs. 7.9 +/- 0.8; P < 0.05) after re-feeding and, at the beginning of PN, their serum aldosterone concentration were also higher (221 +/- 11 vs. 130 +/- 47 pmol/l; P < 0.05). In conclusion, glucose based PN appears to increase sympathetic activity and induce spurious weight gain due to markedly positive wate and sodium balances. Plasma aldosterone concentration at the end of starvation period influences sodium retention and ECW expansion during high glucose re-feeding.

A prospective study of a new protocol for 'in situ' diagnosis of central venous catheter related bacteraemia.

59 patients with suspected central venous catheter related bacteraemia (CRB), while receiving parenteral nutrition, were studied prospectively. 41 (Group 1) were managed conservatively: cultures were taken from the catheter hub lumen, skin at the catheter entry site and peripheral blood; the catheter was then heparinised and locked for 24-48 h. The catheter was withdrawn only if cultures were positive; otherwise parenteral nutrition was resumed. In 18 patients the catheter was immediately withdrawn (Group 2) and the same cultures plus tip culture were performed. 13 patients of Group 1 with positive hub or skin cultures, had their catheters removed and 12 had blood cultures matching for the same micro-organism. Negative skin and hub cultures had a negative predictive value for CRB of 96%. A positive hub culture had a 100% positive predictive value for CRB. CRB was diagnosed in 11 patients out of the 18 in whom catheters were withdrawn immediately (Group 2). Thus, 1 out of 41 catheters and 7 out of 18 catheters were removed unnecessarily in Groups 1 and 2 respectively (p = 0.001, Fisher's test). In all, 24 CRBs were documented and 15 were due to coagulase negative staphylococci. The catheter hub was the commonest origin of CRB followed by the infusate and the skin. In febrile patients on parenteral nutrition, negative skin and hub cultures accurately predict or rule out CRB and should be used more often to avoid withdrawal of sterile catheters.