Adriana Banozic

Dorsal root ganglion - a potential new therapeutic target for neuropathic pain.

A regional approach can protect our patients from often unacceptable adverse effects produced by systematically applied drugs. Regional therapeutic approaches, as well as interventions at the level of the peripheral nervous system and particularly the dorsal root ganglion (DRG), represent an alternative to the systemic application of therapeutic agents. This article provides an overview of DRG anatomical peculiarities, explains why the DRG is an important therapeutic target, and how animal models of targeted drug delivery can help us in the translation of basic research into clinical practice.

Predictors of attrition and academic success of medical students: a 30-year retrospective study.

Aim To determine attrition and predictors of academic success among medical students at University of Split, Croatia. Methods We analysed academic records of 2054 students enrolled during 1979–2008 period. Results We found that 26% (533/2054) of enrolled students did not graduate. The most common reasons for attrition were ‘personal’ (36.4%), transfer to another medical school (35.6%), and dismissal due to unsatisfactory academic record (21.2%). Grade point average (GPA) and study duration of attrition students were significantly associated with parental education. There were 1126 graduates, 395 men and 731 women. Their average graduation GPA was 3.67±0.53 and study duration 7.6±2.44 years. During 5-year curriculum only 6.4% (42/654) of students graduated in time, and 55% (240/472) of students graduated in time after curriculum was extended to 6 years. Variables predicting whether a student will graduate or not were high school grades, entrance exam score and year of enrollment. Significant predictors of graduation grades were high school grades and entrance exam score. Entrance exam score predicted length of studying. Conclusion Preadmission academic qualifications and year of enrollment predict academic success in medical school. More attention should be devoted to high attrition.

Expression of calcium/calmodulin-dependent protein kinase II and pain-related behavior in rat models of type 1 and type 2 diabetes

BACKGROUND:Abnormalities in peripheral nerves and dorsal root ganglia are noticed in the early stage of experimentally provoked diabetic neuropathy. Enzyme calcium/calmodulin-dependent protein kinase II (CaMKII) may have a modulating role in diabetic neuropathy because of its role in calcium homeostasis. METHODS:A model of type 1 diabetes mellitus (DM1) was induced with 55 mg/kg of the streptozotocin and for DM2 induction a combination of high-fat diet and low-dose streptozotocin (35 mg/kg) was used. Pain-related behavior was analyzed using thermal and mechanical stimuli. Two weeks and 2 months after induction of diabetes rats were euthanized, and the expression of CaMKII and its isoforms in the dorsal root ganglia were analyzed using immunofluorescence. RESULTS:Both types of diabetes were successfully induced, as confirmed by hyperglycemia. Increased pain-related behavior became evident in DM1 rats in 2 weeks after diabetes induction, but not in DM2 rats. The expression of total CaMKII and the phosphorylated &agr; isoform of CaMKII increased in DM1 animals concurrently with pain-related behavior. Expression of &agr;, &bgr;, &ggr;, and &dgr; isoforms in DM1 animals and expression of total CaMKII and all of its analyzed isoforms in DM2 animals remained unchanged. CONCLUSIONS:Our findings may indicate involvement of CaMKII in transmission of nociceptive input early in DM1, but not in DM2. CaMKII may be a suitable pharmacological target for diabetic neuropathy.

Sex differences in pain-related behavior and expression of calcium/calmodulin-dependent protein kinase II in dorsal root ganglia of rats with diabetes type 1 and type 2

Sex differences in pain-related behavior and expression of calcium/calmodulin dependent protein kinase II (CaMKII) in dorsal root ganglia were studied in rat models of Diabetes mellitus type 1 (DM1) and type 2 (DM2). DM1 was induced with 55mg/kg streptozotocin, and DM2 with a combination of high-fat diet and 35mg/kg of streptozotocin. Pain-related behavior was analyzed using thermal and mechanical stimuli. The expression of CaMKII was analyzed with immunofluorescence. Sexual dimorphism in glycemia, and expression of CaMKII was observed in the rat model of DM1, but not in DM2 animals. Increased expression of total CaMKII (tCaMKII) in small-diameter dorsal root ganglia neurons, which are associated with nociception, was found only in male DM1 rats. None of the animals showed increased expression of the phosphorylated alpha CaMKII isoform in small-diameter neurons. The expression of gamma and delta isoforms of CaMKII remained unchanged in all analyzed animal groups. Different patterns of glycemia and tCaMKII expression in male and female model of DM1 were not associated with sexual dimorphism in pain-related behavior. The present findings do not suggest sex-related differences in diabetic painful peripheral neuropathy in male and female diabetic rats.

Dental fear and anxiety in older children: an association with parental dental anxiety and effective pain coping strategies.

An association between dental fear and anxiety (DFA) has been confirmed for children younger than 8 years, but this association in older children is less clear. The aim of this study was to fill this knowledge gap by studying DFA in older children and their parents with validated measures. This cross-sectional study, conducted at Community Health Centre Mostar, Bosnia and Herzegovina, included 114 children and their parents. DFA, coping, and sociodemographic variables were studied using Corah Dental Anxiety Questionnaire (CDAS), Dental Subscale of the Children’s Fear Survey Schedule (CFSS-DS), Dental Cope Questionnaire, and sociodemographic questionnaire. Maternal CDAS scores had significant positive correlation with child DFA measured with CFSS-DS (r=0.35, P<0.001) and CDAS (r=0.32, P<0.001). Fathers’ CDAS scores were not associated with child CFSS-DS, but showed a moderate correlation with child CDAS (r=0.19, P<0.05). There were no significant differences in children’s fear and anxiety based on age, sex, or socioeconomic variables. Children used internal coping strategies most frequently and external coping strategies were rated by the children as the most effective. We did not find differences in number and type of effective coping strategies in children with high DFA compared with children with low DFA. In conclusion, there is evidence of the coexistence of dental fear in parents and older children. These findings may help to devise interventions that will prevent or alleviate children’s DFA.

Reduced epidermal thickness, nerve degeneration and increased pain-related behavior in rats with diabetes type 1 and 2.

To examine the mechanisms contributing to pain genesis in diabetic neuropathy, we investigated epidermal thickness and number of intraepidermal nerve fibers in rat foot pad of the animal model of diabetes type 1 and type 2 in relation to pain-related behavior. Male Sprague-Dawley rats were used. Diabetes type 1 was induced with intraperitoneal injection of streptozotocin (STZ) and diabetes type 2 was induced with a combination of STZ and high-fat diet. Control group for diabetes type 1 was fed with regular laboratory chow, while control group for diabetes type 2 received high-fat diet. Body weights and blood glucose levels were monitored to confirm induction of diabetes. Pain-related behavior was analyzed using thermal (hot, cold) and mechanical stimuli (von Frey fibers, number of hyperalgesic responses). Two months after induction of diabetes, glabrous skin samples from plantar surface of the both hind paws were collected. Epidermal thickness was evaluated with hematoxylin and eosin staining. Intraepidermal nerve fibers quantification was performed after staining skin with polyclonal antiserum against protein gene product 9.5. We found that induction of diabetes type 1 and type 2 causes significant epidermal thinning and loss of intraepidermal nerve fibers in a rat model, and both changes were more pronounced in diabetes type 1 model. Significant increase of pain-related behavior two months after induction of diabetes was observed only in a model of diabetes type 1. In conclusion, animal models of diabetes type 1 and diabetes type 2 could be used in pharmacological studies, where cutaneous changes could be used as outcome measures for predegenerative markers of neuropathies.

Parents’ Pain Catastrophizing is Related to Pain Catastrophizing of Their Adult Children

BackgroundParents’ pain behavior is associated with the way their children experience and express pain.PurposeWe hypothesized that there is a positive association between levels of pain catastrophizing in parents and their adult children.MethodStudy included 285 participants, 100 patients, 85 spouses, and 100 adult children from 100 families. Pain catastrophizing was assessed with the Croatian version of Pain Catastrophizing Scale. Patients’ pain intensity was measured with the visual analogue scale.ResultsSignificant positive correlation was found between pain catastrophizing of adult children and both of their parents. Regression analysis was conducted to test for the role of parents’ pain catastrophizing scores in explaining pain catastrophizing in their adult children. The results showed that parents’ pain catastrophizing scores explain results of their adult children, accounting for 20% of the variance.ConclusionThe results from the present study indicate that there is a positive association between levels of pain catastrophizing in parents and their adult children. A family may have a specific cognitive style for coping with pain, which is associated to a child’s responses to pain experiences.

Intrathecal inhibition of calcium/calmodulin-dependent protein kinase II in diabetic neuropathy adversely affects pain-related behavior.

Calcium/calmodulin-dependent protein kinase II (CaMKII) is considered an important enzyme contributing to the pathogenesis of persistent pain. The aim of this study was to test whether intrathecal injection of CaMKII inhibitors may reduce pain-related behavior in diabetic rats. Male Sprague-Dawley rats were used. Diabetes was induced with intraperitoneal injection of 55mg/kg streptozotocin. Two weeks after diabetes induction, CaMKII inhibitor myristoil-AIP or KN-93 was injected intrathecally. Behavioral testing with mechanical and thermal stimuli was performed before induction of diabetes, the day preceding the injection, as well as 2h and 24h after the intrathecal injection. The expression of total CaMKII and its alpha isoform in dorsal horn was quantified using immunohistochemistry. Intrathecal injection of mAIP and KN-93 resulted in significant decrease in expression of total CaMKII and CaMKII alpha isoform activity. Also, mAIP and KN93 injection significantly increased sensitivity to a mechanical stimulus 24h after i.t. injection. Intrathecal inhibition of CaMKII reduced the expression of total CaMKII and its CaMKII alpha isoform activity in diabetic dorsal horn, which was accompanied with an increase in pain-related behavior. Further studies about the intrathecal inhibition of CaMKII should elucidate its role in nociceptive processes of diabetic neuropathy.

Pain catastrophizing changes during the menstrual cycle

Pain catastrophizing is an important predictor of pain intensity and pain-related outcomes. Many studies have shown that the level of this phenomenon is higher in women compared to men. The aim of this study was to investigate whether there is a difference in pain catastrophizing in women during the different phases of their menstrual cycle and whether there is a difference in pain catastrophizing depending on the history of childbirth and dysmenorrhea. A prospective study was conducted among 149 healthy women aged 18–35, with a regular menstrual cycle, 80 of which were nulliparous. The participants filled a sociodemographic questionnaire at the enrollment and the Pain Catastrophizing Scale on the 1st, 12th, and 20th day of the menstrual cycle. Pain catastrophizing scores, including all the subscales, significantly varied throughout the menstrual cycle, being highest on the first day of menstrual cycle and declining subsequently. Pain catastrophizing scores were higher in nulliparous than in parous women. Higher pain catastrophizing scores on the first day of the menstrual cycle were found in dysmehorrhoic women and women who regularly use analgesics for dysmenorrhea. Knowing that pain catastrophizing varies throughout the menstrual cycle may help in creating interventions for pain prevention and treatment in cycling women.

Risk factors associated with postoperative pain after ophthalmic surgery: a prospective study

Background Risk factors associated with postoperative pain intensity and duration, as well as consumption of analgesics after ophthalmic surgery are poorly understood. Methods A prospective study was conducted among adults (N=226) who underwent eye surgery at the University Hospital Split, Croatia. A day before the surgery, the patients filled out questionnaires assessing personality, anxiety, pain catastrophizing, sociodemographics and were given details about the procedure, anesthesia, and analgesia for each postoperative day. All scales were previously used for the Croatian population. The intensity of pain was measured using a numerical rating scale from 0 to 10, where 0 was no pain and 10 was the worst imaginable pain. The intensity of pain was measured before the surgery and then 1 hour, 3 hours, 6 hours, and 24 hours after surgery, and then once a day until discharge from the hospital. Univariate and multivariate analyses were performed. Results A multivariate analysis indicated that independent predictors of average pain intensity after the surgery were: absence of premedication before surgery, surgery in general anesthesia, higher pain intensity before surgery and pain catastrophizing level. Independent predictors of postoperative pain duration were intensity of pain before surgery, type of anesthesia, and self-assessment of health. Independent predictors of pain intensity ≥5 during the first 6 hours after the procedure were the type of procedure, self-assessment of health, premedication, and the level of pain catastrophizing. Conclusion Awareness about independent predictors associated with average postoperative pain intensity, postoperative pain duration, and occurrence of intensive pain after surgery may help health workers to improve postoperative pain management in ophthalmic surgery.