The Impact of Chronic Stress on Behavior and Body Mass in New Animal Models.

(1) Background: Exposure to different sources of stress can have a significant effect on both psychological and physical processes. (2) Methods: The study took place over a period of 34 days and included a total of 40 animals. Regarding the exposure to chronic stressors, we opted for physiological, non-invasive stressors, e.g., running, swimming, and changes in the intensity of light. An unforeseen stress batch was also created that alternated all these stress factors. The animals were divided into five experimental groups, each consisting of eight individuals. In the context of conducting the open field test for behavioral assessment before and after stress exposure, we aimed to investigate the impact of stress exposure on the affective traits of the animals. We also monitored body mass every two days. (3) Results: The control group exhibited an average increase in weight of approximately 30%. The groups exposed to stress factors showed slower growth rates, the lowest being the running group, recording a rate of 20.55%, and the unpredictable stress group at 24.02%. The anxious behavior intensified in the group with unforeseen stress, in the one with light variations, and in the running group. (4) Conclusions: Our research validates the animal model of intermittent light exposure during the dark phase as a novel method of inducing stress. The modification of some anxiety parameters was observed; they vary according to the type of stress. Body mass was found to increase in all groups, especially in the sedentary groups, likely due to the absence of cognitive, spatial, and social stimuli except for cohabitation.

Checkpoint inhibitors in NSCLC for the elderly: current challenges and perspectives.

Introduction: In the elderly non-small cell lung cancer (NSCLC) is more commonly diagnosed in advanced stages. Conservative therapy including chemotherapy in this age group might be challenging because one of the criteria for its indication is the appropriate functional status, and in the elderly this is more difficult to ascertain. Checkpoint inhibitors are recent therapies found to be effective alone or in combinations in patients with advanced NSCLC, but little is known about their efficacy and their safety in such patients.Areas covered: We review clinical studies of checkpoint inhibitors in patients with advanced NSCLC in an attempt to identify peculiarities related to their use in the elderly. The clinical studies discussed enrolled a significant proportion of elderly patients and for some compounds, post-hoc analysis in the elderly was performed. Efficacy data supports the use of such compounds in the elderly and the safety profile is acceptable for all molecules discussed.Expert opinion: In the elderly with advanced NSCLC, checkpoint inhibitors are efficacious and well tolerated and may be appropriate for use in patients with an increased impaired functional status. Furthermore, in this category of patients this therapy may be used as a neoadjuvant therapy in order to improve the resectability of the tumor.

THE EFFECT OF COBALT CHLORIDE PRECONDITIONING ON PACLITAXEL-INDUCED PERIPHERAL NEUROPATHY.

INTRODUCTION: Recent studies indicate that Cobalt Chloride (CoC12) modulates mitochondrial activity. There is emerging data suggesting that Paclitaxel-induced peripheral neuropathy (PIPN) is a consequence of the drug's mitochondrial toxicity. AIM: to assess the effect of CoC12 preconditioning on PIPN in an animal model. MATERIAL AND METHOD: PIPN was induced by 7 daily consecutive i.p. Paclitaxel (PXT) administrations. Male BALB/c mice were divided into three groups as follows: group A--CoC12 (12.5 mg/kg b.w.) for three weeks (preconditioning) followed by I week of PXT, group B--saline for three weeks, followed by 1 week of PXT and group C--saline for four weeks. Thermal and mechanical allodynia were assessed by means of paw withdrawal latency (PWL). RESULTS: In group A, CoC12 preconditioning lead to a decrease in both thermal and mechanical PWLs. 7 days after the last dose of PXT, however, values returned to normal in group A and allodynia for both thermal and mechanical stimuli was noted in group B (p < 0.05). CONCLUSIONS: CoC12 preconditioning seems to protect against PIPN. Although CoC12 administration decreased thermal and mechanical PWLs, subsequent P administration did not lead to the persistent mechanical and thermal allodynia that was noted in the P-alone group. Further studies are required for determining the exact relationship between CoC12 and PIPN.

THE EFFECTS OF RIBOFLAVIN AND METHYLENE BLUE ON NOCICEPTION AND VISCERAL PAIN.

BACKGROUND: Methylene Blue (MB) can prevent electron leaking, increase mitochondrial oxidative phosphorylation, and reduce ROS overproduction under pathological conditions, currently being trace evidence that it can alter pain perception in humans by local administration during certain surgical procedures. Riboflavin or vitamin B2 (B2) constitutes a part of the vitamin B group, which in recent studies shows a growing implication in the treatment of some pathology that imply pain management. AIM: To investigate the effect of one dose of Riboflavin and Methylene Blue on nociception and visceral pain in mice. METHODS: A total of 48 BALB/c male mice were divided into 3 groups: MB Group, B2 Group and C Group. MB (5 mg/kg b.w.), B2 (100 mg/kg b.w.) or an equivalent volume of saline was administered intraperitoneally. Mice were tested before (baseline) and after drugs administration over a 4h period. Nociception was evaluated by means of Hot Plate Test (HPT) and TFT (Tail Flick Test). Visceral pain was evaluated 2h after administration. RESULTS: Four hours after MB administration we recorded an analgesic effect on the hot plate test (p < 0.05 at 30, 60 and 240 min). No significant effect on the TFT was noticed. B2 vitamin had an antinociceptive effect as compared to control group only for HPT that persisted for 2h but had no effect on TFT. Both MB and B2 vitamin have shown an analgesic effect (p < 0.01) on visceral pain when compared to the control group but the pain inhibition was more important after riboflavin administration. CONCLUSIONS: Even if the exact mechanisms are not clarified by our study, we demonstrated that both ATP modulators (MB & B2 vitamin) have analgesic effect on visceral pain and nociception.

Enhanced analgesic effects of tramadol and common trace element coadministration in mice.

Chronic pain is managed mostly by the daily administration of analgesics. Tramadol is one of the most commonly used drugs, marketed in combination with coanalgesics for enhanced effect. Trace elements are frequent ingredients in dietary supplements and may enhance tramadol's analgesic effect either through synergic mechanisms or through analgesic effects of their own. Swiss Weber male mice were divided into nine groups and were treated with a combination of the trace elements Mg, Mn, and Zn in three different doses and a fixed dose of tramadol. Two groups served as positive (tramadol alone) and negative (saline) controls. Nociceptive assessment by tail-flick (TF) and hot-plate (HP) tests was performed at baseline and at 15, 30, 45, and 60 min after intraperitoneal administration. Response latencies were recorded and compared with the aid of ANOVA testing. All three trace elements enhanced tramadol's analgesic effect, as assessed by TF and HP test latencies. Coadministration of these trace elements led to an increase of approximately 30% in the average pain inhibition compared with the tramadol-alone group. The most effective doses were 0.6 mg/kg b.w. for Zn, 75 mg/kg b.w. for Mg, and 7.2 mg/kg b.w. for Mn. Associating trace elements such as Zn, Mg, and Mn with the standard administration of tramadol increases the drug's analgesic effect, most likely a consequence of their synergic action. These findings impact current analgesic treatment because the addition of these trace elements may reduce the tramadol dose required to obtain analgesia.

Preconditioning with cobalt chloride modifies pain perception in mice.

Cobalt chloride (CoCl2) modifies mitochondrial permeability and has a hypoxic-mimetic effect; thus, the compound induces tolerance to ischemia and increases resistance to a number of injury types. The aim of the present study was to investigate the effects of CoCl2 hypoxic preconditioning for three weeks on thermonociception, somatic and visceral inflammatory pain, locomotor activity and coordination in mice. A significant pronociceptive effect was observed in the hot plate and tail flick tests after one and two weeks of CoCl2 administration, respectively (P<0.001). Thermal hyperalgesia (Plantar test) was present in the first week, but recovered by the end of the experiment. Contrary to the hyperalgesic effect on thermonociception, CoCl2 hypoxic preconditioning decreased the time spent grooming the affected area in the second phase of the formalin test on the orofacial and paw models. The first phase of formalin-induced pain and the writhing test were not affected by CoCl2 preconditioning. Thus, the present study demonstrated that CoCl2 preconditioning has a dual effect on pain, and these effects should be taken into account along with the better-known neuro-, cardio- and renoprotective effects of CoCl2.

Incidence of chemotherapy discontinuation and characteristics of elderly patients with non-small cell lung cancer treated with platinum-based doublets.

AIM OF THE STUDY: To compare patient's characteristics, clinical data, and rates of chemotherapy discontinuation in advanced NSCLC (non-small cell lung cancer) patients treated with platinum-based association chemotherapy (elderly vs. younger counterparts). To evaluate if there are certain factors that can predict discontinuation of chemotherapy. MATERIAL AND METHODS: A retrospective analysis of all cases of advanced NSCLC treated with either cisplatin-gemcitabine or cisplatin-vinorelbine at the Regional Institute of Oncology Iasi between January 2012 and December 2013 was performed. Patients were divided into two groups: over 70 years old and under 70 years old. Patient's characteristics and clinical data (including whether or not the patient discontinued treatment) were recorded for each case. RESULTS: The elderly patients had more comorbidities (p = 0.003), were prescribed a larger number of pills (p = 0.02), and had longer periods of hospitalisation (p = 0.005). No difference in toxicity was noted between the two groups. Five patients chose to discontinue chemotherapy in the elderly group. Only two patients made the same choice (p = 0.02) in the younger group. Correlation analysis revealed that refusal of further chemotherapy was associated with the length of hospital stay, number of pills per day, and smoking status. CONCLUSIONS: Geriatricians should minimise iatrogeny and polypharmacy by optimising long-term treatment. This will increase the chance that elderly patients will not discontinue chemotherapy. Hospital stay should be reduced to a minimum. As life span increases so does the number of elderly patients with cancer; it is vital to understand and prevent the causes of chemotherapy discontinuation in order to achieve optimal therapeutic results.

Pain modulation by curcumin and ascorbic acid in mice.

AIM: The present study aims to evaluate whether ascorbic acid (AA) and curcumin, two substances with redox properties, have similar effects on different models of pain in mice. MATERIALS AND METHODS: This study included a total of 28 mice that were divided into four groups. One group (AA) received intraperitoneally 500 mg/kg b.w. AA for 21 days and the 2-nd group (curcumin) received 120 mg/kg b.w. curcumin by gastric gavage for two weeks. Other two groups serve as control and received vehicle in a dose--time manner similar to that of the treated groups. The pain models (oro-facial formalin induced pain, paw formalin induced pain and visceral pain) were performed 24 h after the last dose. RESULTS: When compared with control groups, curcumin significantly decreases pain perception in oro-facial (p = 0.01 1-st phase, p = 0.002 2-nd phase) and paw formalin induced pain (p = 0.04 1-st and 2-nd phase) while AA stimulates pain perception in acid acetic induced visceral pain (p = 0.05) and increases oro-facial inflammatory pain induced by formalin ( p = 0.02) but demonstrates analgesic effects on paw formalin induced pain (p = 0.003 1-st phase, p = 0.01 2-nd phase). CONCLUSIONS: ROS production is important in pain modulation. Structures involved in the process of pain have different antioxidant defense capacities. Curcumin and AA are able to modulate pain perception, but beside their antioxidant capacities, there are other mechanisms involved.

Leishmaniasis--an unusual cause of splenomegaly in Romania.

Leishmaniasis is a parasitic infection caused by protozoans classified as Leishmania species. Romania is not considered an endemic country and there are only few reports of sporadic cases in the last 100 years. However, studies suggest that the disease is spreading north. We present the case of a 44 year old female that presented with asthenia, perspirations, vertigo, weight loss and menometrorhagias in small to medium quantity. Clinical exam revealed the presence of splenomegaly and her blood tests indicated she had pancitopenia; differential diagnosis included myeloproliferative or lymphoproliferative disorders, infections that evolve with spleen enlargement, autoimmune-related splenomegaly and hepatic--all tests were negative. She refused the bone marrow aspiration. Three months later, her condition worsened and the menometrorragias became more severe. Bone marrow aspiration revealed the presence of numerous intra and extracellular Leishmania spp. amastigotes. A detailed anamnesis showed that she had worked for six months in Italy as a care-giver nine months ago. She was transferred to Bucharest where she received optimal treatment. However, due to the continuous bleeding, the evolution was unfavourable. This is an alarm sign for physicians that should take into account the fact that, due to population migration and global warming, tropical infectious diseases are becoming more and more common. The signs and symptoms, as well as the treatment in leishmaniasis are reviewed, as well as a brief history of leishmaniasis in Romania.

Macro-creatine kinase syndrome as an underdiagnosed cause of ck-mb increase in the absence of myocardial infarction: two case reports.

When assessing an acute coronary syndrome (ACS) by means of high serum levels of creatine kinase (CK) and its MB fraction (CK-MB), one must keep in mind that there are several other causes for an increase of these markers, such as myocarditis, pericarditis, heart failure, severe aortic stenosis, stroke, renal failure, malignant hyperthermia, Reye syndrome, polymyositis, and borreliosis (1). Also, there are cases when CK-MB is falsely increased due to certain abnormalities that occur in the CK isoenzymes. One such example is the formation of the so-called macro-creatine kinase complexes (macro-CK) that give a false increase of the CK-MB fraction. We report two clinical cases where macro-CK was the cause of apparent increase in serum CK and CK-MB: in a 79-year old male with a history of coronary disease and a 82-year old female with permanent atrial fibrillation.