On the role of agonist-evoked Ca2+ mobilization in sustaining the ongoing phosphoinositide hydrolysis

Stimulation of SK-N-BE(2) cells with 1 mM carbachol (Cch) elicited phosphoinositide (PPI) hydrolysis and a rapid elevation of cytosolic Ca²⁺ concentration ([Ca²⁺]_i) from 115 nM to about 500 nM, followed by a plateau around 200 nM. In myo [³H]inositol-labelled cells, Cch-evoked accumulation of [³H]inositol phosphates (IPs) was not affected when [Ca²⁺]_i was clamped at resting by cell loading with 10 M BAPTA/AM; under these conditions, maximal 1,4,5-inositol trisphosphate accumulation was not reduced either. When [Ca²⁺]_i was clamped around 700 nM by cell treatment with 600 nM ionomycin, Cch-evoked [³H]IPs accumulation was enhanced by less than 20%, but it was impaired by a 30% and a 55% after [Ca²⁺]_i reduction to about 70 nM and 35—50 nM, by cell loading with 20 M or 40 M BAPTA/AM, respectively. These results show that, in SK-N-BE(2) cells, Cch-activated PPI-specific phospholipase C is sensitive to [Ca²⁺]_i but it already operates under suboptimal conditions at resting [Ca²⁺]_i.     

Relationship between plasma and bone concentrations of cefuroxime and flucloxacillin three different parenteral administrations compared in 30 arthroplasties

• (i) The objective was to determine the range of bone levels of cefuroxime and flucloxacillin achieved after one intravenous (IV) administration of different dosages of cefuroxime and flucloxacillin.
• (ii) Six groups of five patients participated in the study. The first three groups (A–C) received respectively 1500 mg, 1000 mg, and 500 mg cefuroxime intravenously and the second three groups (D–F) received 2000 mg, 1500 mg, and 1000 mg flucloxacillin intravenously.
• (iii) Parenteral administration of cefuroxime and flucloxacillin resulted in measurable bone concentrations in all patients.
• (iv) Large inter-individual variation in bone concentration was observed.
• (v) The bone concentrations of IV cefuroxime were higher (1500 mg, p = 0.0057; 1000 mg, p = 0.0260) than those of flucloxacillin. The bone concentrations of cefuroxime and flucloxacillin were dose dependent.

     

Stabilization of rat serum proteins following oral administration of fish oil

The mechanism of action of fish oil (FO), currently used in different chronic inflammatory conditions such as rheumatoid arthritis (RA), is not completely understood, although it is thought that it could alter the metabolism of endogenous autacoids. In addition, we hypothesized that the known capability of fatty acids (FA) of stabilizing serum albumin and perhaps other proteins, may be of pharmacological relevance considering that it is shared by other anti-rheumatic agents (e.g. nonsteroidal antiinflammatory drugs). Thus, we studied the effect of oral administration of FO and corn oil (CO), a vegetable oil with a different composition, on the stability of rat serum proteins, evaluated by a classical in vitro method based on heat-induced protein denaturation. FO, and, to a lower extent, CO inhibited heat-induced denaturation of rat serum (RS): based on the inhibitory activity (EC50) of the major fatty acids against heat-induced denaturation of RS in vitro, it was possible to speculate that in vivo effects of palmitic acid (C16:0) and eicosapentaenoic acid (EPA, C20:5, n-3) may be more relevant than that of linolenic acid (C18:2). To better investigate this phenomenon, we extracted albumin from the serum of animals treated or not with FO with a one-step affinity chromatography technique, obtaining high purity rat serum albumin preparations (RSA-CTRL and RSA-FO), as judged by SDS-PAGE with Coomassie blue staining. When these RSA preparations were heated at 70 degrees C for 30 min, it was noted that RSA-FO was much more stable than RSA-CTRL, presumably due to higher number of long chain fatty acids (FA) such as palmitic acid or EPA. In conclusion, we provided evidences that oral administration of FO in the rat stabilizes serum albumin, due to an increase in the number of protein bound long chain fatty acids (e.g. palmitic acid and EPA). We speculate that the stabilization of serum albumin and perhaps other proteins could prevent changes of antigenicity due to protein denaturation and glycosylation, which may trigger pathological autoimmune responses, suggesting that this action may be involved in the mode of action of FO in RA and other chronic inflammatory diseases.     

Neo-adjuvant organ-preserving chemotherapy in the management of locally advanced oral cavity and oropharynx cancer

We designed an open, non-randomized clinical study to assess as the first endpoint the feasibility of sparing surgery and of preserving organ/function by using neo-adjuvant chemotherapy (NAG) in oral cavity and oropharynx cancer patients, and, as the second endpoint, the clinical response to this treatment approach and its duration. Moreover, an attempt was made to scale the extent of surgery by means of an Arbitrary Scale assigning different percentages to the different extents of surgical resection. Twenty-five patients with primary oral cavity and oropharynx cancer (stage III-TV) were enrolled in the study and were assigned to either the classical Al-Sarrafs regimen (1) (n=15) or to a regimen (2) consisting of cisplatin 80 mg/m(2) i.v. on day 1, 5-FU 600 mg/m(2) on days 2-5 and vinorelbine 20 mg/m(2) on days 2 and 8 (n=10). The 25 patients were all evaluable for response to NAC and 20 of them were evaluable for organ preservation. The overall response (OR) rate was 86.6% (13/15 patients) for regimen 1 (cisplatin + 5-FU) and 80% (8/10 patients) for regimen 2 (cisplatin + 5-FU + vinorelbine). The median follow-up duration was 20.6 months. 5/20 (25%) patients completely avoided surgery, 5/20 (25%) patients had a reduced extent of surgical resection, while: 10/20 (50%) patients received the previously planned surgical resection. Altogether, 10/20 (50%) patients treated with NAC either avoided or achieved a reduction in the previously planned surgical resection. Moreover, organ function was evaluated to support the assessment of treatment outcome in our patients. For this purpose we selected the Performance Status Scale for Head and Neck Cancer Patients: as expected, no significant impairment was detected in the area of comprehensibility of speech, but we were rather surprised that no significant impairment was found in the two areas of eating in public and normalcy of diet. NAG-associated toxicity was moderate and similar in the two chemotherapy regimens. The most relevant contributions offered by our study are represented by i) a Scale aimed at measuring as precisely as possible the reduction of surgical resection made possible by NAC compared to surgery planned before NAC and ii) an attempt to support the results with an assessment of treatment outcome.     

Evaluation of the specificity of the leukocyte migration inhibition test against histologically homologous and heterologous neoplastic antigens in cancer patients

The aim of the present study was to verify whether the CMI response of the host's lymphocytes is directed towards tumor-associated antigens (TAA) specific for each histological type of tumor. The leucocyte migration inhibition (LMI) test was selected for this purpose, utilizing the cancer patients' leucocytes and, as neoplastic antigens, formalin-fixed cells of surgically removed cancer tissue. Two hundred and eighteen patients were studied, 110 of whom were affected by breast cancer, 48 by digestive tract and 60 by laryngeal cancer. The total amount of tests performed was 278. The leucocytes of 93 normal subjects were tested against the different tissues' cancer antigens, as were the leucocytes of 41 patients with cancer of different organs tested against the corresponding normal tissues' antigens. The breast cancer patients (122 tests performed) showed 82.35% positive tests against homologous antigen, 72.72% and 95.24% against heterologous (digestive tract and laryngeal cancer, respectively) antigens. The digestive tract cancer patients (69 tests performed) showed 70.27% positive tests against homologous, 66.66% and 43.48% against heterologous antigens (breast and laryngeal cancer respectively). The laryngeal cancer patients (87 tests performed) showed 74.29% positive tests against homologous, 38.10% and 80.65% against heterologous antigens (breast and digestive tract, respectively). The results led to the conclusion that the LMI test response of cancer patients was not "tissue specific": the test did not discriminate between the homologous and the heterologous cancer antigens, and it seems that the response was not directed towards specific TAA but only towards wide-range or "group" TAA, showed by several types of tumors.     

Evaluation of depression in patients with alzheimer's disease according to the location of medical care

The objective of the study was to assess the severity of depression and to assess the level of self-sufficiency of patients with Alzheimer's disease, with particular emphasis on the place of residence and level of education. The study covered 90 people diagnosed with Alzheimer's disease. All respondents were persons over 65?years of age and residents of cities with a population over one-hundred thousand. The research method based on this work is the author's own questionnaire, the Zung Self-Rating Depression Scale (ZSDS) about depression and the Karnofsky Performance Scale Index (KPSI) for assessment of a patient's self-sufficiency. Regardless of residence, patients with Alzheimer's disease displayed signs of mild or moderate depression (100% in social welfare homes and hospital patients and 60% in those with caregivers at home). Patients with Alzheimer's disease have an unsatisfactory salary in social-economic terms. In those with Alzheimer's disease, quality of life is best for those in family homes under the care of their immediate family. People with a vocational education were the largest group of people diagnosed with Alzheimer's. Patients at home and in the hospital had a higher level of physical activity, but most patients in the hospital needed regular medical care, as did patients in social welfare homes.     

Surgical treatment of pleural empyema in Coronavirus disease 19 patients: the Southern Switzerland experience

We report the first surgical series of patients developing pleural empyema after severe bilateral interstitial lung disease in confirmed severe acute respiratory syndrome coronavirus 2 infection. The empyema results in a complex medical challenge that requires combination of medical therapies, mechanical ventilation and surgery. The chest drainage approach was not successful to relieve the symptomatology and to drain the excess fluid. After multidisciplinary discussion, a surgical approach was recommended. Even though decortication and pleurectomy are high-risk procedures, they must be considered as an option for pleural effusion in Coronavirus disease-positive patients. This is a life-treating condition, which can worsen the coronavirus disease manifestation and should be treated immediately to improve patient’s status and chance of recovery.     

A neuropathology-based approach to epilepsy surgery in brain tumors and proposal for a new terminology use for long-term epilepsy-associated brain tumors

Every fourth patient submitted to epilepsy surgery suffers from a brain tumor. Microscopically, these neoplasms present with a wide-ranging spectrum of glial or glio-neuronal tumor subtypes. Gangliogliomas (GG) and dysembryoplastic neuroepithelial tumors (DNTs) are the most frequently recognized entities accounting for 65 % of 1,551 tumors collected at the European Epilepsy Brain Bank (n = 5,842 epilepsy surgery samples). These tumors often present with early seizure onset at a mean age of 16.5 years, with 77 % of neoplasms affecting the temporal lobe. Relapse and malignant progression are rare events in this particular group of brain tumors. Surgical resection should be regarded, therefore, also as important treatment strategy to prevent epilepsy progression as well as seizure- and medication-related comorbidities. The characteristic clinical presentation and broad histopathological spectrum of these highly epileptogenic brain tumors will herein be classified as “long-term epilepsy associated tumors—LEATs”. LEATs differ from most other brain tumors by early onset of spontaneous seizures, and conceptually are regarded as developmental tumors to explain their pleomorphic microscopic appearance and frequent association with Focal Cortical Dysplasia Type IIIb. However, the broad neuropathologic spectrum and lack of reliable histopathological signatures make these tumors difficult to classify using the WHO system of brain tumors. As another consequence from poor agreement in published LEAT series, molecular diagnostic data remain ambiguous. Availability of surgical tissue specimens from patients which have been well characterized during their presurgical evaluation should open the possibility to systematically address the origin and epileptogenicity of LEATs, and will be further discussed herein. As a conclusion, the authors propose a novel A–B–C terminology of epileptogenic brain tumors (“epileptomas”) which hopefully promote the discussion between neuropathologists, neurooncologists and epileptologists. It must be our future mission to achieve international consensus for the clinico-pathological classification of LEATs that would also involve World Health Organization (WHO) and the International League against Epilepsy (ILAE).