Near-fatal cerebellar swelling caused by acute multifocal cerebellar necrosis.

We report a case of acute near-fatal cerebellar swelling, which was accompanied by multifocal cerebellar necrosis. Acute, near-fatal cerebellar swelling is a rare problem thought to be of parainfectious aetiology. Initiation by multifocal cerebellar necrosis has not been reported so far with this disorder.     

Phase I pharmacological and bioavailability study of oral diflomotecan (BN80915), a novel E-ring-modified camptothecin analogue in adults with solid tumors.

PURPOSE: Diflomotecan (BN80915) is an E-ring modified camptothecin analogue that possesses greater lactone stability in plasma compared with other topoisomerase I inhibitors, a potential advantage for antitumor activity. As with other camptothecins, oral administration has pharmacological and clinical advantages. This Phase I study was performed to assess the feasibility of the administration of oral diflomotecan, to determine the maximum-tolerated, dose its bioavailability, and to explore the pharmacokinetics. EXPERIMENTAL DESIGN: An initial i.v. bolus was administered to assess the bioavailability of diflomotecan. Fourteen days later, diflomotecan was administered p.o. once daily for 5 days to adult patients with solid malignant tumors and repeated every 3 weeks. BN80915 and its open lactone form BN80942 were measured. RESULTS: Twenty-two patients entered the study and received a total of 57 cycles of oral diflomotecan at flat dose levels of 0.10, 0.20, 0.27, and 0.35 mg. The main toxicity was hematological, but some patients experienced alopecia, mild gastrointestinal toxicity, and fatigue. At the 0.35-mg dose level, 2 of 4 patients experienced dose-limiting toxicity comprising grade 3 thrombocytopenia with epistaxis and febrile neutropenia in 1 patient and uncomplicated grade 4 neutropenia lasting for >7 days in another. Toxicity was acceptable at the 0.27-mg dose level at which dose-limiting toxicities were observed in 3 of 12 patients (grade 4 neutropenia > 7 days, complicated by fever in 1 patient but without other signs of infection). After two cycles of diflomotecan, 6 patients had disease stabilization, which was maintained in 2 patients for 9 months and >1 year, respectively. Diflomotecan pharmacokinetics were linear over the dose range studied. Systemic exposure correlated with the fall in WBC counts. The mean oral bioavailability (+/-SD) was 72.24 +/- 59.2% across all dose levels. Urinary excretion of BN80915 was very low. CONCLUSIONS: The recommended oral diflomotecan dose for Phase II studies is 0.27 mg/day x 5 every 3 weeks. This regimen is convenient and generally well tolerated with a favorable pharmacokinetic profile and high but variable bioavailability.     

Fibrinolytic activity of earthworms extract (g-90) on lysis of fibrin clots originated from the venous blood of patients with malignant tumors

u-PA is secreted by the most malignant tumors. As a response to u-PA synthesis surrounding cells synthetize inhibitors of plasminogen activators for tissue protection. Plasminogen activators were found also in earthworm tissue. From the tissue homogenate of earthworm Eisenia foetida the glycolipoprotein mixture named G-90 was isolated. It contains two serine proteases (P I, P II) with fibrinolytic and anticoagulative activities. The fibrinolytic activity of G-90, P I and P II was tested in an in vitro euglobulinic test applied to fibrin clot from blood plasma of patients suffered from malignant tumors. G-90 and above-mentioned proteases applied in this study showed euglobulinic time proportionally with the concentrations of added substances. The influence of G-90 on the fibrinolysis rate does not depend only on its concentration, but depends too on histological type of tissue (organ) where the malignant tumors are located. Enzyme P I and P II do not show this activity.     

Joint effect of commercial preparations of Stevia rebaudiana Bertoni and sodium monoketocholate on glycemia in mice.

A study was made of the combined effect of two commercial products of Stevia rebaudiana Bertoni and sodium monoketocholate (mkc) on blood glucose concentration in mice. One group of animals was treated four days with mkc, 4 mg/kg, s.c., second with 200 mg/kg, i.p., of Stevita (Stevita Co, INC, Arlington, Texas) (stevia), third with 20 mg/kg, i.p., of Clear Steviosides Liquid (Stevita Co, INC, Herbal supplement, Brazil) (stevioside), fourth with the combination of stevia and mkc, and the fifth with stevisode and mkc. Blood glucose concentration was measured before treatment, after the first and fourth dose, as well as after subjecting animals to glucose-tolerance test (500 mg/kg, p.o.) or provoking glycemia by injecting adrenaline (0.2 mg/kg, s.c.). It was found that one dose of stevioside combined with mkc caused a significant increase of glycemia with respect of mkc alone and control (10.80:7.90:8.01). However, when repeated four days, the same pretreatment resulted in a significant decrease of glycemia compared with single-dose pretreatment (10.80:7.20). The increase in glycemia with the mice that received four doses of stevioside and mkc and then were subjected to glucose-tolerance test was significantly lower compared to that in mice that were pretreated four days only with mkc before receiving glucose (6.33:7.80). Analogous difference was observed between the animals given mkc alone and mkc plus stevioside after injecting adrenaline (13.33:10.54). As for the interaction of mkc and stevia it was found that the combined pretreatment yielded lower values of glycemia compared with that measured after treatment with stevia alone (6.40:7.82).     

The construction of the Split Sleep Questionnaire on sleep habits during the COVID-19 pandemic in the general population

AimTo construct a single-format questionnaire on sleep habits and mood before and during the COVID-19 pandemic in the general population.MethodsWe constructed the Split Sleep Questionnaire (SSQ) after a literature search of sleep, mood, and lifestyle questionnaires, and after a group of sleep medicine experts proposed and assessed questionnaire items as relevant/irrelevant. The study was performed during 2021 in 326 respondents distributed equally in all age categories. Respondents filled out the SSQ, the Pittsburgh Sleep Quality Index (PSQI), and State Trait Anxiety Inventory (STAI), and kept a seven-day sleep diary.ResultsWorkday and work-free day bedtime during the COVID-19 pandemic assessed with SSQ were comparable to the sleep diary assessment (P = 0.632 and P = 0.203, respectively), as was the workday waketime (P = 0.139). Work-free day waketime was significantly later than assessed in sleep diary (8:19 ± 1:52 vs 7:45 ± 1:20; P < 0.001). No difference in sleep latency was found between the SSQ and PSQI (P = 0.066). Cronbach alpha for Sleep Habits section was 0.819, and 0.89 for Mood section. Test-retest reliability ranged from 0.45 (P = 0.036) for work-free day bedtime during the pandemic to 0.779 (P < 0.001) for sleep latency before the pandemic.ConclusionThe SSQ provides a valid, reliable, and efficient screening tool for the assessment of sleep habits and associated factors in the general population during the COVID-19 pandemic.

The COVID-19 pandemic, along with its multiple adverse effects on various aspects of mental health, has significantly affected sleep. Sleep habits alterations and newly developed sleep disturbances during the COVID-19 pandemic may influence the overall well-being and health (1). Since the beginning of the pandemic, several studies reported a delay in bedtimes and waketimes, and an associated shift in chronotype toward eveningness (2-5).Even though actigraphy and sleep diaries provide a valid and reliable assessment of sleep habits (6,7), to achieve the highest reliability and validity, these methods require an assessment during seven consecutive days including weekends (8). Daily reporting may be perceived by the respondents as an additional burden (6,9), a limitation that may be overcome by the use of single-administration questionnaires (9,10). Since sleep disturbances recognized in the first pandemic outbreak remained stable during new waves of the COVID-19 pandemic (5), single-administration questionnaires may enable screening of large population groups and an extended assessment of sleep disturbances during the pandemic.So far, validated sleep questionnaires have most often aimed at sleep disorders or symptoms associated with sleep disorders (9). Studies commonly report the Pittsburgh sleep Quality Index (PSQI) (11), which provides data on sleep duration, sleep disturbances, and sleep latency during the previous month. However, PSQI reflects mainly sleep quality on workdays (12), while not collecting information on sleep habits on weekends. The Sleep Timing Questionnaire (STQ) has been developed as an alternative to the sleep diary for the healthy adult population, showing good reliability and validity (10). Still, although sleep habits are associated with mood (13), social media use (14-16), learning time in students (17-19), sports or exercise (20), and symptoms of insomnia (21), the STQ does not assess variables such as mood and lifestyle habits.Large studies objectively assessing sleep with wearable devices have recognized sleep timing and sleep duration to be modifiable risk factors for adverse mental health during the current pandemic (22). Young adults are especially at risk for increased mood disorder symptoms, higher levels of perceived stress, and more common alcohol use during the pandemic (23). Even though mood disorders are often reported in pandemic studies on sleep habits, mood itself has been less commonly measured and associated with sleep parameters (24). A review of the literature showed a transactional relationship between mood and emotion (25), indicating that mood is characterized by longer duration than emotion (26). Mood is often assessed with the Brief Mood Introspection Scale (27), the Profile of Mood States (28), or the Visual Analogue Mood Scale (29). A relevant aspect of mood measurement is a hierarchical structure with two broad dimensions in positive and negative affect, and multiple specific states (30). Commonly used mood assessment scales evaluate the basic negative mood of fear/anxiety, sadness/depression, and anger/hostility, as well as at least one positive mood. Therefore, it has been strongly recommended that mood researchers assess a broad range of both positive and negative emotions (30).Linking mood changes and lifestyle habits during the pandemic has been relevant in order to recognize possible predictors of mood changes, especially due to a reported increase in depression (31). Since sleep is often intertwined with mood and lifestyle changes (31), we assumed that a single-format questionnaire comprehensively assessing these variables and sleep may be applicable and timely.The aim of this study was to construct a single-format Split Sleep Questionnaire (SSQ) comprehensively assessing sleep habits, lifestyle habits, and mood changes, as well as to evaluate its reliability and validity in the general population. Sleep habits were validated by using standard instruments such as sleep diary, PSQI, and STAI questionnaires as the measures of construct validity. Additionally, we aimed to assess the psychometric properties of the Mood section and to explore the effects of the COVID-19 pandemic on sleep habits and mood alterations in the general population of Croatia.     

Alterations in geometry,biomechanics, and mineral composition of juvenile rat femur induced by nonplanar PCB‐155 and/or planar PCB‐169

Exposure to widespread lipophilic and bioaccumulative polychlorinated biphenyls (PCBs) induces diverse biochemical and toxicological responses in various organs, including the bone. The aim of this study was to evaluate the changes in growth rate, geometry, serum, and bone biochemical parameters and biomechanics of juvenile rat femur induced by lactational exposure to nonplanar PCB‐155 and planar PCB‐169 individually and in combination. Fifteen lactating Wistar rats were divided into four groups (PCB‐169, PCB‐155, PCB‐155+169, and control), and PCBs were administered intraperitoneally at different time points after delivery. Femurs from 22‐day‐old offspring were analyzed by microCT, three‐point bending test and inductively coupled plasma‐mass spectrometry (ICP‐MS) to obtain data on bone geometry, biomechanics and mineral composition. The serum levels of calcium, phosphate and alkaline phosphatase were also determined. Lactational exposure to planar PCB‐169 resulted in shorter and thinner femurs, reduced endosteal and periosteal perimeters, smaller total cross‐sectional and medullary areas, and lowered serum bone marker levels and calcium levels in the bone, while femur mechanical properties were not significantly altered. The changes observed in the combination exposure (PCB‐155+169) group were similar to those observed in the PCB‐169 group but were less pronounced. In summary, our results demonstrate that alterations in lactationally exposed offspring were primarily induced by planar PCB‐169. The milder outcome in the combined group suggested that the PCB‐169‐mediated toxic effects on the bone might be reduced by a nonplanar PCB‐155 congener. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1135–1146, 2017.     

Inhibition of AMPK-dependent autophagy enhances in vitro antiglioma effect of simvastatin

The role of autophagy, a process in which the cell self-digests its own components, was investigated in glioma cell death induced by the hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase-inhibiting drug simvastatin. Induction of autophagy and activation of autophagy-regulating signalling pathways were analyzed by immunoblotting. Flow cytometry/fluorescent microscopy was used to assess autophagy-associated intracellular acidification and apoptotic markers (phosphatidylserine exposure, DNA fragmentation and caspase activation). Cell viability was determined by crystal violet, MTT or LDH release assay. Simvastatin treatment of U251 and C6 glioma cell lines caused the appearance of autophagolysosome-like intracytoplasmic acidic vesicles. The induction of autophagy in U251 cells was confirmed by the upregulation of autophagosome-associated LC3-II and pro-autophagic beclin-1, as well as by the downregulation of the selective autophagic target p62. Simvastatin induced the activation of AMP-activated protein kinase (AMPK) and its target Raptor, while simultaneously downregulating activation of Akt. Mammalian target of rapamycin (mTOR), a major AMPK/Akt downstream target and a major negative autophagy regulator, and its substrate p70 S6 kinase 1 were also inhibited by simvastatin. Mevalonate, the product of HMG-CoA reductase enzymatic activity, AMPK siRNA or pharmacological inactivation of AMPK with compound C suppressed, while the inhibitors of Akt (10-DEBC hydrochloride) and mTOR (rapamycin) mimicked autophagy induction by simvastatin. Inhibition of autophagy with bafilomycin A1, 3-methyladenine and LC3β shRNA, as well as AMPK inhibition with compound C or AMPK siRNA, markedly increased apoptotic death of simvastatin-treated U251 cells. These data suggest that inhibition of AMPK-dependent autophagic response might sensitize glioma cells to statin-induced apoptotic death.     

Three-dimensional assessment of palatal area changes after posterior crossbite correction with tooth-borne and tooth bone–borne rapid maxillary expansion: A randomized controlled trial with 5-year follow-up

ObjectivesTo assess and compare the three-dimensional treatment changes in palatal surface area and volume using either tooth-borne (TB) or tooth bone–borne (TBB) rapid maxillary expanders and to evaluate the long-term effects of the two devices and the incidence of the relapse between the groups.Materials and MethodsA total of 52 consecutive patients who met the eligibility criteria were recruited and allocated to either the TB group, mean age 9.3 years (standard deviation [SD], 1.3), or the TBB group, mean age 9.5 years (SD, 1.2). Study casts were taken before, directly after, 1 year after, and 5 years after expansion. Study casts were digitized, superimposed, and evaluated. Participants were randomly allocated in blocks of different sizes using the concealed allocation principle in a 1:1 ratio.ResultsChanges in palatal volume, palatal surface area, and palatal projection area within and between the groups up to 5 years after expansion followed the same pattern and did not show any statistically significant differences between the groups. Relapse was seen in 15% of the patients. It seemed that open-bite and a Class III growth pattern could be assumed as prognosis-deteriorating factors in regard to stability of the treatment.ConclusionsThere were no significant differences between the TB and TBB groups in palatal volume, palatal shell area, or palatal projection area directly after expansion or at 1 year and 5 years after expansion, which implies that the two devices gave rise to the same immediate and long-term outcomes.     

【In Press】Lyme Borrelia as the etiological factor in three cases of primary inflammatory choriocapillaropathies

Letter to the editor