New fracture patterns distal epiphysis femur in youth: Update of current classification.

INTRO: Distal growth core fractures of the femur are the third most common fracture in patients older than 10 years. These fractures result from high-energy trauma and have a high risk of evolving into growth disorders. The classification most used to describe these types of fractures is that described by Salter and Harris. Special clinical cases often occur in clinical practice that are not described in the classifications used. In our study, we analyzed and further focused on new fracture patterns related to pediatric epiphyseal detachments not easily described by the normal classifications currently used in the literature. MATERIALS AND METHODS: From January 2020 to December 2022, we treated 2 male clinical cases with epiphyseal detachments of the distal femur that could not be classified according to the Salter and Harris classification. age of the patients was 10 and 11 years, respectively; for both patients, the traumatic mechanism was a direct trauma to the right knee at high speed using an electric scooter; Serious clinical and radiographic follow-ups were performed at month 1, month 3, month 6, month 12, and month 24 from the date of surgery. DISCUSSION: Distal femur fractures represent a challenge for the orthopedics because they have a high incidence of complications. In our experience, there has been an increase in this type of injury caused using recently developed electric vehicles, which can reach considerable speeds. The Salter Harris classification is among the most widely used for fractures involving the growth physis. This classification proved to be rather limiting in the present case, so we decided to classify the fracture as 'Salter Harris III equivalent'. CONCLUSIONS: The fracture examined is a very rare fracture of the distal femur and is not reflected in the classifications currently in use. The patient presented an excellent clinical and radiographic result after surgery with the presence of a shortening of the affected femur in relation to the contralateral one, which suggests that the growth deficit may continue and increase over time for which reason future studies until skeletal maturity will be necessary to quantify the damage to the growth physis.

Redox modulation of stress resilience by Crocus sativus L. for potential neuroprotective and anti-neuroinflammatory applications in brain disorders: From molecular basis to therapy.

Recent evidence demonstrates that Crocus sativus L. (saffron) counteracts oxidative stress, mitochondrial dysfunction and neuroinflammation, closely linked to initiation and progression of major brain pathologies. Interestingly, saffron constituents such as crocin, crocetin and safranal can exert antioxidant or toxic effects depending on their endogenous concentration. According to the hormesis principles, at low dose they act as antioxidants in a wide range of brain diseases by upregulating Nrf2 signaling pathway and the expression of vitagenes, such as NAD(P)H-quinone oxidoreductase (NQO1), glutathione transferase (GT), heme oxygenase-1 (HO-1), sirtuin-1 (Sirt1) and thioredoxin (Trx) system. Importantly, neuronal dysregulation of Nrf2 pathway can be a prominent cause of selective susceptibility, under neuroinflammatory conditions, due to the high vulnerability of brain cells to oxidative stress. Here we discuss natural inducers from saffron targeting Nrf2/vitagene pathway for development of new therapeutical strategies to suppress oxidative stress and neuroinflammation and consequently cognitive dysfunction. In this review we also focus on the hormetic effect of saffron active constituents, summarizing their neuroprotective and anti-neuroinflammatory properties, as well as pharmacological perspectives in brain disorders.

Vascular endothelial growth factor monitoring in advanced hepatocellular carcinoma patients treated with radiofrequency ablation plus octreotide: a single center experience.

Local therapies such as radiofrequency ablation (RFA) represent a valuable choice in limited hepatocellular carcinoma (HCC) and are increasingly used also in advanced tumors. Medical treatments generally gave frustrating results in advanced HCC especially if comorbidities exist. Several biologic non-chemotherapeutic drugs are currently tested in HCC and, among them, octreotide was evaluated in single series of HCC patients reporting conflicting results. We have treated a series of 35 patients affected by advanced HCC (26 M and 9 F; age range: 55-85 years, median: 73 years) with RFA followed by octreotide to primarily evaluate the safety of combined treatment and to give preliminary evaluation on its activity. We have also evaluated serum VEGF changes during the study. Child A and Child B represented 60% and about 34% of the cases, respectively. Only two patients with Child C compensated cirrhosis were included in this study. All patients have multiple liver HCC nodules and one had bone metastases. Two complete responses, 3 partial responses and 23 disease stabilization for at least three months were obtained (overall response rate, 14,2%; clinical benefit, 80%). Mean overall survival was 31.4 months. The combined treatment was well tolerated. Statistically significant correlation was found between serum VEGF and tumor progression. In conclusion, the combination of RFA and octreotide was active in advanced HCC, however, confirmation in a larger series is required.

Extracellular Tau Oligomers Produce An Immediate Impairment of LTP and Memory.

Non-fibrillar soluble oligomeric forms of amyloid-ß peptide (oAß) and tau proteins are likely to play a major role in Alzheimer's disease (AD). The prevailing hypothesis on the disease etiopathogenesis is that oAß initiates tau pathology that slowly spreads throughout the medial temporal cortex and neocortices independently of Aß, eventually leading to memory loss. Here we show that a brief exposure to extracellular recombinant human tau oligomers (oTau), but not monomers, produces an impairment of long-term potentiation (LTP) and memory, independent of the presence of high oAß levels. The impairment is immediate as it raises as soon as 20 min after exposure to the oligomers. These effects are reproduced either by oTau extracted from AD human specimens, or naturally produced in mice overexpressing human tau. Finally, we found that oTau could also act in combination with oAß to produce these effects, as sub-toxic doses of the two peptides combined lead to LTP and memory impairment. These findings provide a novel view of the effects of tau and Aß on memory loss, offering new therapeutic opportunities in the therapy of AD and other neurodegenerative diseases associated with Aß and tau pathology.

The keystone of Alzheimer pathogenesis might be sought in Aß physiology.

For several years Amyloid-beta peptide (Aß) has been considered the main pathogenetic factor of Alzheimer's disease (AD). According to the so called Amyloid Cascade Hypothesis the increase of Aß triggers a series of events leading to synaptic dysfunction and memory loss as well as to the structural brain damage in the later stage of the disease. However, several evidences suggest that this hypothesis is not sufficient to explain AD pathogenesis, especially considering that most of the clinical trials aimed to decrease Aß levels have been unsuccessful. Moreover, Aß is physiologically produced in the healthy brain during neuronal activity and it is needed for synaptic plasticity and memory. Here we propose a model interpreting AD pathogenesis as an alteration of the negative feedback loop between Aß and its physiological receptors, focusing on alpha7 nicotinic acetylcholine receptors (α7-nAchRs). According to this vision, when Aß cannot exert its physiological function a negative feedback mechanism would induce a compensatory increase of its production leading to an abnormal accumulation that reduces α7-nAchR function, leading to synaptic dysfunction and memory loss. In this perspective, the indiscriminate Aß removal might worsen neuronal homeostasis, causing a further impoverishment of learning and memory. Even if further studies are needed to better understand and validate these mechanisms, we believe that to deepen the role of Aß in physiological conditions might represent the keystone to elucidate important aspects of AD pathogenesis.

Object memory enhancement by combining sub-efficacious doses of specific phosphodiesterase inhibitors.

The second messengers cGMP and cAMP have a vital role in synaptic plasticity and memory processes. As such, phosphodiesterases inhibitors (PDE-Is), which prevent the breakdown of these cyclic nucleotides, represent a potential treatment strategy in memory decline. Recently it has been demonstrated that cGMP and cAMP signaling act in sequence during memory consolidation, with early cGMP signaling requiring subsequent cAMP signaling. Here, we sought to confirm this relationship, and to evaluate its therapeutic implications. Combining sub-efficacious doses of the cGMP-specific PDE type 5 inhibitor vardenafil (0.1 mg/kg) and cAMP-specific PDE type 4 inhibitor rolipram (0.01 mg/kg) during the early and late memory consolidation phase, respectively, led to improved memory performance in a 24 h interval object recognition task. Similarly, such a sub-efficacious combination treatment enhanced the transition of early-phase long-term potentiation (LTP) to late-phase LTP in hippocampal slices. In addition, both object memory and LTP were improved after administration of two sub-efficacious doses of the dual substrate PDE type 2 inhibitor BAY60 7550 (0.3 mg/kg) at the early and late consolidation phase, respectively. Taken together, combinations of sub-efficacious doses of cAMP- and cGMP-specific PDE-Is have an additive effect on long-term synaptic plasticity and memory formation and might prove a superior alternative to single PDE-I treatment.

Improvement of diabetic autonomic gustatory sweating by botulinum toxin type A.

Fourteen diabetic subjects with gustatory sweating were treated by intracutaneous injections of botulinum toxin type A into the affected facial skin areas. In all subjects, sweating (measured by Minor starch iodine test) ceased within 4 days, with the maximal follow-up time lasting 24 weeks. This therapeutic approach, which could be used to reduce the severity of diabetic gustatory sweating, appears to be long lasting, adverse effect free, and minimally invasive.

Concomitant depression of locus coeruleus neurons and of flexor reflexes by an alpha 2-adrenergic agonist in rats: a possible mechanism for an alpha 2-mediated muscle relaxation.

The alpha 2-agonist tizanidine, clinically used as an antispastic drug, also strongly reduces polysynaptic flexor reflexes. The hypothesis was tested that the noradrenergic coerulespinal system exerts a tonic facilitation on spinal reflexes and that the depressant effects of tizanidine may be explained by an alpha 2-mediated autoinhibition of the tonic activity of locus coeruleus neurons, resulting in a disfacilitation of the spinal reflexes. The following results support this working hypothesis: (1) systemic injections of tizanidine markedly decreased the spontaneous activity of locus coeruleus neurons, but not of non-locus coeruleus neurons. The alpha 2-antagonist yohimbine reversed this effect. (2) The time course of diminished locus coeruleus activity paralleled that of depressed flexor reflexes. (3) Flexor reflexes were also markedly depressed by the alpha 1-adrenergic antagonist prazosin, administered alone, which is in line with the proposition that the noradrenergic system exerts a tonic facilitation on spinal neurons by way of alpha 1-adrenergic receptor activation. (4) Flexor reflexes were facilitated by conditioning microstimulation of locus coeruleus neurons, and this effect was reversed by prazosin. (5) Flexor reflexes significantly diminished in size following placement of an irreversible lesion in the ipsilateral locus coeruleus. Although these results strongly support the above hypothesis regarding a descending modulatory function of the descending locus coeruleus system on spinal reflexes, possible additional mechanisms, perhaps also involving the ascending projection of the locus coeruleus to supraspinal motor structures, remain to be elucidated.

Motor cortex modulation of exteroceptive information at bulbar and thalamic lemniscal relays in the cat.

We have studied the control of the primary motor cortex on the activity of lemniscal neurons in semi-chronic implanted cats. In each experiment, two to three foci in the primary motor cortex were identified by intracortical microstimulation at low threshold (up to 20 microA) for their capacity to evoke movements of contralateral single limb joints. Neurons belonging to the dorsal column nuclei (main cuneate nucleus and gracile nucleus), or to the ventral posterolateral nucleus, were sampled for their response to stimulation of the peripheral cutaneous fields, as well as the antidromic response to stimulation of the contralateral medial lemniscus and ipsilateral somatosensory cortex, respectively. These neurons were then tested for stimulation of the cortical foci using a current intensity equal to the threshold needed to evoke motor effects, although we reduced the duration of the stimulating trains; thus, we avoided evoking movements which could elicit afferent volleys along the somatosensory paths. It was found that the primary motor cortex was able to modulate the transmission of exteroceptive signals at the level of both dorsal column nuclei and ventral posterolateral nucleus with analogous modalities. In particular: (i) a high percentage of responses, with a prevalence of excitatory effects, was observed when the receptive field of the neurons topographically corresponded to, or was very close to, the joint controlled by a given cortical focus; (ii) in these cases, higher percentages of excitations were observed in tests which concerned the distal segments of limbs than the proximal segments; (iii) the percentage of responses became lower as the neuronal receptive field was located further from the cortical motor target, the pattern being more frequently inhibitory in nature. From a functional point of view, the motor cortex control appears to be organized in a very precise manner. Its excitatory nature might subserve integrative mechanisms by which exteroceptive information arising in a given limb segment would be enhanced by a motor command inducing movements of the same body part. Moreover, a better definition of the afferent input could be obtained by a simultaneous depression of neurons, which send towards the cortex signals from adjacent or more distant cutaneous regions. It can be hypothesized that such an organization of the cortical control could improve the discriminative somatosensory aspects during the execution of explorative movements, besides supplying a sharper cutaneous feedback to the motor cortex.

Drugs in nails: physiology, pharmacokinetics and forensic toxicology.

In recent years, drug analysis in keratinised matrices, such as hair and nails, has received considerable attention because of several advantages over drug testing methodologies employing body fluids, such as urine or serum. For example, keratinic matrices, such as finger- and toenails, can accumulate drugs during long term exposure. Drugs are incorporated into nails by a double mechanism: (i) deposition into the root of the growing nail via the blood flow in the nail matrix; and (ii) incorporation via the nail bed during growth from the lunula to the beginning of the free margin. Together, these account for a wide retrospective window of drug detection. Nails can provide a good forensic matrix for the detection of drugs of abuse. Indeed, the international literature has reported the use of nail analysis in postmortem detection of drugs of abuse, drug testing in the workplace and drug screening to detect prenatal exposure, even though further studies are needed for correct interpretation of the data obtained. Another application of drug analysis in nails consists of the possibility of detecting the presence of an antimycotic at the site of action during antifungal therapy for patients with onychomycosis. When available, this evidence has permitted drug treatment of a shorter duration and reduced toxicity. However, so far the potential of drug monitoring in nails still lacks harmonisation and validation of analytical methodologies and a better comprehension of the possible correlation between drug concentrations in the matrix and period of exposure.

What is the role of the supplementary motor area in movement initiation?

The hierarchical position of the supplementary motor area (SMA) relative to the primary motor cortex is discussed on the basis of neurological observations and of animal experiments. In the last 10 years evidence has accumulated, especially from studies on the human brain, that the supplementary motor area is a hierarchically superior structure involved in the processes of movement initiation. Single unit studies in subhuman primates also revealed neuronal populations related to aspects of movement preparation rather than to the movement per se. However, we report that a surprisingly large subpopulation of SMA neurones has features classically found in the primary motor cortex (MI). These MI-like neurones precede movement onset by a relatively short interval. The occurrence of such "short-lead neurones" was somewhat higher in MI, but the histograms of lead-times were completely overlapping in the two areas. Taken together with the fact that the SMA is microexcitable and is part of the origin of the pyramidal tract, these findings suggest that the SMA functions also in parallel with MI as concluded by Woolsey and coworkers (1952). Finally, the SMA and MI are reciprocally interconnected, a situation which is not unlike that of the cortical visual areas.

Studies on the structure of sperm heads of Eledone cirrhosa by means of CLSM linked to bioimage-oriented devices.

We have used a confocal laser scanning optical microscope imaging device and a bioimage-oriented workstation equipped for augmented reality to study the helical sperm head of the octopus Eledone cirrhosa. This approach allows us to study different complex organisational motifs due to the spatial arrangement of linear helical structures. We consider this helical specimen an enlarged copy of one of the most important biostructures governing cell functioning such as chromatin-DNA. Moreover, this very same sample is made of highly compacted chromatin that can be studied at higher resolution, i.e., by means of scanning force microscopy. Fluorescence optical sectioning has been used to enter the spatial organisation. Three-dimensional images of single, twisted, and folded fibers are shown.

Modulatory action of noradrenergic system on spinal motoneurons in humans.

Previous findings in animals demonstrated that the noradrenergic coeruleospinal system exerts a tonic facilitation on spinal reflexes and that activation of alpha2-autoinhibitory receptors can be responsible for a disfacilitation of the spinal activity. To investigate this issue further, we examined whether this system is also involved in descending facilitatory control of spinal motoneurons in healthy humans. The H-reflex technique was utilized to assay the motoneuronal excitability. The ratio between the maximal reflex response (H) and maximal direct response (M) was determined in each subject and was calculated at 10 min intervals before and after i.v. administration of the alpha2-agonist clonidine (0.5 microg/kg). In all subjects a marked decrease of the H/M ratio, due to depression of the H response, occurred 10 min following the clonidine injection and reached its maximum within 30 min. No significant changes of blood pressure values were provoked by drug injections. These results suggest that an autoinhibitory action may be induced by alpha2-receptor activation of locus coeruleus neurons in humans, and that this device may serve as a mechanism for a myotonolytic action on spinal motoneurons.

Convergence pattern of cortical and interposital influences on rubrospinal neurons of the cat.

In adult semi-chronically implanted sedated cats discharges of single rubrospinal (RS) neurons were tested for selective activation of movement-evoking foci within pericruciate cortex (CX; area 4) and anterior division of cerebellar interpositus nucleus (IN). It was found that a very high incidence of neuronal responses was obtained only when stimulating IN and CX foci which controlled the same joint with respect to that moved from activation of the rubral foci including the recorded neurons. In these cases very frequent convergence phenomena were observed by activating IN and/or CX foci. Analysis of response patterns showed that RS neurons included in a focus controlling a given muscle were excited by IN foci for the same muscle (agonist foci) and inhibited from IN foci for the antagonist muscle (antagonist foci). In contrast, the same RS neurons were inhibited by agonist CX foci and excited by antagonist CX foci. Such an organization suggests that the motor cortex plays a competitive role in modulating the action of the interposito-rubrospinal system.

Involvement of the noradrenergic system in modulating the blink reflex in humans.

Several researches have shown that the spinal reflex transmission in animals, as well as humans, was inhibited by alpha(2)-agonists, due to a disfacilitation of tonic noradrenergic control on motoneuronal output. To understand better the mechanisms regulating certain aspects of motor activity, here we reinvestigated the possible role of noradrenergic systems in modulating reflex activity of the brainstem in humans. To this aim, blink reflex responses (R1 and R2) evoked by electrical stimulation of the supraorbital nerve were electromyographically recorded in healthy volunteers. Both R1 and R2 areas were measured at 10-min intervals before and after i.v. injection of alpha(2)-agonist clonidine (0.5 microg/kg). The substance induced consistent depression of R1, which reached its maximum 40 min after drug administration (-43% of the control values). Ipsilateral R2 area resulted little affected by clonidine (-15% at 50 min), whereas no effects were observed in contralateral R2. Blood pressure values were never altered by drug injections. These results, taken together with previous observations, support the hypothesis that alpha(2)-agonist substances may cause a transient inactivation of noradrenergic neurons, thus releasing neurons involved in the circuitry of the blink reflex from a facilitatory drive. Since clonidine differentially modulated blink reflex responses, it is likely to assume that such a disfacilitation concerns mostly pontine units mediating the R1. However, the complexity of clonidine's effects at multiple pre- and postsynaptic sites does not allow us to exclude that other systems are involved in the alpha(2)-mediated control of facial motoneurons.

Analgesic activity of a synthetic analogue of eel-calcitonin and its effect on the spontaneous activity of brainstem neurons in the rat.

Intracerebroventricular (i.c.v.) injection of (Asul,7)eel-calcitonin, a synthetic analogue of eel-calcitonin, at doses of 3 or 6 IU/rat, (but not at 1.5 IU/rat) determined analgesic activity, in male rats, as evaluated by the 'hot-plate' test. Also electrophysiological studies carried out on 13 neurons belonging to the nucleus raphe magnus (NRM) showed that i.c.v. administration of the same doses of (Asul,7)eel-calcitonin increased the spontaneous cellular firing rate. No modification of the discharge frequency was observed when 1.5 IU/rat (Asul,7)eel-calcitonin was used. Authors suggest that the analgesic activity induced by i.c.v. injection of (Asul,7)eel-calcitonin is due, at least in part, to mechanisms affecting NRM neurons.

The feasibility of the detection and quantitation of beta-adrenergic blockers by solid-phase extraction and subsequent derivatization with methaneboronic acid.

Urine specimens containing 11 common beta blockers were processed using solid-phase extraction technology to extract the drugs from the urine matrix, then converted to their cyclic methaneboronates by treatment with methaneboronic acid in ethyl acetate. The compounds tested included acebutolol, atenolol, alprenolol, bisoprolol, betaxolol, carteolol, penbutolol, propranolol, pindolol, timolol, nadolol, sotalol, labetolol, metoprolol, and oxprenolol. The extraction efficiencies were greater than 90% for all drugs tested. The cyclic methaneboronates formed by this procedure generally possessed good chromatographic properties. The mass spectral behavior of the methaneboronates was excellent, with all compounds containing several high mass fragments and every tested compound possessing a unique mass spectrum.

Effects of short-term reserpine treatment on generalized and focal dystonic-dyskinetic syndromes.

We report that low dose reserpine treatment (0.25 mg/day for 7 days) improves the dystonic-dyskinetic disability score in patients affected by idiopathic dystonias, iatrogenic dystonic-dyskinetic syndromes and Sydenham's chorea. The results support the idea that the particular antidopaminergic activity exerted by reserpine or other dopamine-depleting agents may produce good therapeutical efficacy, although reserpine can precipitate Parkinsonism and induce dopamine-receptor supersensitivity.

Unilateral enhancement of early and late blink reflex components in hemidystonia.

The side-to-side differences in the EMG activity of the early and late components of blink reflex, regarded as revealing the state of excitability of the brain stem reflex centers, have been analyzed in patients with unilateral dystonia without demonstrable brain lesions. It has been observed that both early and late responses of direct blink reflex were higher on the side affected by hemidystonia than on the contralateral one, while the latency values were in the normal range. Possibility that an abnormal output from the striatum towards the brainstem structures involved in blink reflex appears on the affected side of hemidystonic patients is discussed.

Excitatory amino acids as neurotransmitters of corticostriatal projections: immunocytochemical evidence in the rat.

The retrograde transport of a tracer has been combined with peroxidase immunocytochemistry to verify whether corticostriatal (CS) neurons contain in their cell bodies high levels of glutamate (Glu) and aspartate (Asp). Injections of WGAapoHRP-Au in the caudate/putamen of adult rats produced retrograde labeling of a large number of layer V neurons of wide regions of the ipsilateral cerebral cortex; fewer labeled neurons were also found on the contralateral side. In all experiments, most CS neurons were seen in the agranular frontal cortex, in both the medial and the lateral subdivisions. Moreover, numerous retrogradely labeled neurons were observed in the cingulate cortex and in the granular parietal cortex, depending on the location of the injection site in the various experiments. The majority of CS neurons examined were immunostained using antibodies against glutaraldehyde-conjugates of Glu or Asp. Glu immunopositive neurons resulted 52-61% of CS neurons. Asp immunopositive neurons ranged between 53% and 62%. In the cortical tissue where Glu and Asp antisera were visualized simultaneously, up to 96% of the CS neurons were immunostained. The latter finding indicates that the populations of Glu and Asp immunopositive neurons are largely segregated and that virtually all cortical neurons projecting to the striatum contain high concentrations of Glu and/or Asp, thus corroborating the hypothesis that CS projections use excitatory amino acids as neurotransmitters.