Fractional order controllers increase the robustness of closed-loop deep brain stimulation systems.

We studied the effects of using fractional order proportional, integral, and derivative (PID) controllers in a closed-loop mathematical model of deep brain stimulation. The objective of the controller was to dampen oscillations from a neural network model of Parkinson's disease. We varied intrinsic parameters, such as the gain of the controller, and extrinsic variables, such as the excitability of the network. We found that in most cases, fractional order components increased the robustness of the model multi-fold to changes in the gains of the controller. Similarly, the controller could be set to a fixed set of gains and remain stable to a much larger range, than for the classical PID case, of changes in synaptic weights that otherwise would cause oscillatory activity. The increase in robustness is a consequence of the properties of fractional order derivatives that provide an intrinsic memory trace of past activity, which works as a negative feedback system. Fractional order PID controllers could provide a platform to develop stand-alone closed-loop deep brain stimulation systems.

Centripetal focusing of gyrotactic phytoplankton.

A suspension of gyrotactic microalgae Chlamydomonas augustae swimming in a cylindrical water vessel in solid-body rotation is studied. Our experiments show that swimming algae form an aggregate around the axis of rotation, whose intensity increases with the rotation speed. We explain this phenomenon by the centripetal orientation of the swimming direction towards the axis of rotation. This centripetal focusing is contrasted by diffusive fluxes due to stochastic reorientation of the cells. The competition of the two effects lead to a stationary distribution, which we analytically derive from a refined mathematical model of gyrotactic swimmers. The temporal evolution of the cell distribution, obtained via numerical simulations of the stochastic model, is in quantitative agreement with the experimental measurements in the range of parameters explored.

Sodium hyaluronate improves quality of life and nasal endoscopy features in preschool children with upper respiratory tract infections.

The aim of this prospective, randomised study was to evaluate the effects of nasal douches with sodium hyaluronate on clinical and endoscopic variables, on parental perception of their child’s health-related quality of life (HR-QoL), and on parental workdays lost in preschool recurrent upper respiratory tract infections (URTIs). Children aged 2-6 years with recurrent or persistent URTIs underwent at baseline the evaluation of upper respiratory tract symptoms in the previous two weeks, and nasal endoscopy. Parents of enrolled children were assessed for self-perception of their children’s HR-QoL using a standardised questionnaire. The same variables were reassessed after a 2-week treatment with either 9 mg sodium hyaluronate plus saline solution or saline alone by nasal douches. Forty of the 48 children enrolled completed the study (22 assigned to the combined treatment). Compared to baseline, the combined treatment resulted in a significant reduction of the prevalence of children with missed daycare days (45% vs 14%, p=0.04) and of parents with workdays lost (36% vs 5%, p=0.02), and in a significant improvement of HR-QoL score (3.7 vs 2.8, p=0.004). At endoscopy, the secretion and mucosal oedema score significantly improved after the combined treatment (6 vs 2, p < 0.001), and there was a trend towards a reduction of the adenoid hypertrophy score (p=0.06). No clinical, HR-QOL or endoscopy changes were found in the saline group. In preschool children with recurrent or persistent URTIs, sodium hyaluronate by nasal douche significantly improves endoscopic features. Additional benefits include the children’s HR-QoL and daycare attendance, and parental work.

Treatment of patients with BRAFV600E-mutated metastatic colorectal cancer after progression to encorafenib and cetuximab: data from a real-world nationwide dataset.

BACKGROUND: Targeted therapy (TT) with encorafenib and cetuximab is the current standard for patients with BRAFV600E-mutated metastatic colorectal cancer (mCRC) who received one or more prior systemic treatments. However, the median progression-free survival (mPFS) is ∼4 months, and little is known about the possibility of administering subsequent therapies, their efficacy, and clinicopathological determinants of outcome. METHODS: A real-world dataset including patients with BRAFV600E-mutated mCRC treated with TT at 21 Italian centers was retrospectively interrogated. We assessed treatments after progression, attrition rates, and outcomes. RESULTS: Of the 179 patients included, 85 (47%), 32 (18%), and 7 (4%) received one, two, or three lines of treatment after TT, respectively. Those receiving TT in the second line were more likely to receive at least one subsequent therapy (53%), as compared with those treated with TT in the third line or beyond (30%; P < 0.0001), and achieved longer postprogression survival (PPS), also in a multivariate model (P = 0.0001). Among 62 patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) tumors receiving one or more lines of treatment after second-line TT, combinatory chemotherapy ± anti-vascular endothelial growth factor (anti-VEGF) was associated with longer PFS and PPS as compared with trifluridine-tipiracil or regorafenib (mPFS: 2.6 versus 2.0 months, P = 0.07; PPS: 6.5 versus 4.4 months, P = 0.04). CONCLUSIONS: Our real-world data suggest that TT should be initiated as soon as possible after the failure of first-line treatment in BRAFV600E-mutated mCRC. Among patients with pMMR/MSS tumors, combinatory chemotherapy ± anti-VEGF appears the preferred treatment choice after TT failure.

Near-unity quantum yields of biexciton emission from CdSe/CdS nanocrystals measured using single-particle spectroscopy.

Biexciton photoluminescence (PL) quantum yields (Q(2X)) of individual CdSe/CdS core-shell nanocrystal quantum dots with various shell thicknesses are derived from independent PL saturation and two-photon correlation measurements. We observe a near-unity Q(2X) for some nanocrystals with an ultrathick 19-monolayer shell. High Q(2X)'s are, however, not universal and vary widely among nominally identical nanocrystals indicating a significant dependence of Q(2X) upon subtle structural differences. Interestingly, our measurements indicate that high Q(2X)'s are not required to achieve complete suppression of PL intensity fluctuations in individual nanocrystals.

Mutations in DNAH5 account for only 15% of a non-preselected cohort of patients with primary ciliary dyskinesia.

BACKGROUND: Primary ciliary dyskinesia (PCD) is characterised by recurrent infections of the upper respiratory airways (nose, bronchi, and frontal sinuses) and randomisation of left-right body asymmetry. To date, PCD is mainly described with autosomal recessive inheritance and mutations have been found in five genes: the dynein arm protein subunits DNAI1, DNAH5 and DNAH11, the kinase TXNDC3, and the X-linked retinitis pigmentosa GTPase regulator RPGR. METHODS: We screened 89 unrelated individuals with PCD for mutations in the coding and splice site regions of the gene DNAH5 by denaturing high performance liquid chromatography (DHPLC) and sequencing. Patients were mainly of European origin and were recruited without any phenotypic preselection. RESULTS: We identified 18 novel (nonsense, splicing, small deletion and missense) and six previously described mutations. Interestingly, these DNAH5 mutations were mainly associated with outer + inner dyneins arm ultrastructural defects (50%). CONCLUSION: Overall, mutations on both alleles of DNAH5 were identified in 15% of our clinically heterogeneous cohort of patients. Although genetic alterations remain to be identified in most patients, DNAH5 is to date the main PCD gene.

[Measles and its secondary pulmonary complications: prevention is better than treatment]. / Il morbillo e le sue complicanze polmonari secondarie: prevenire è meglio che curare.

Recent measles outbreaks observed in North America and in several European countries, including Italy, raised the attention about the risks linked to this infection and the need of implementing and maintaining adequate preventive strategies. Measles may cause several respiratory complications such as chronic obstructive lung disease, pneumonia, with subsequent development of chronic suppurative lung disease, giant cells pneumonia or progressive respiratory insufficiency. The current preventive strategies aim to improve vaccination coverage rates with 2 doses of measles-mumps and rubella vaccine, and to catch up individuals who have not been previously vaccinated. The present review analyses pulmonary complications of measles and measles preventive strategies. Elimination of measles is a feasible goal. Since measles complications are preventable by vaccination, improvement in vaccination coverage is highly desirable.

Upper airway obstructive disease in mucopolysaccharidoses: polysomnography, computed tomography and nasal endoscopy findings.

In mucopolysaccharidoses, upper airway obstruction has multiple causative factors and progressive respiratory disease may severely affect morbidity and mortality. In a cross-sectional study over 2 years we evaluated upper airway obstructive disease through overnight polysomnography, upper airway computed tomography and nasal endoscopy in 5 children and 6 adults with mucopolysaccharidoses of various types. Measurements of apnoea and apnoea-hypopnoea index, arousal index, and sleep efficiency were obtained through polysomnography. Retropalatal and retroglossal spaces were calculated through computed tomography, and the degree of adenoid hypertrophy was assessed through endoscopy. Apnoea index and apnoea-hypopnoea index were significantly higher in children than in adults with mucopolysaccharidoses (p = 0.03 and p = 0.03, respectively). Compared to healthy controls, retropalatal and retroglossal spaces were significantly smaller in children (p = 0.03 and p = 0.004, respectively) or adults with mucopolysaccharidoses (p = 0.004 and p = 0.004, respectively). All subjects had adenoid hypertrophy causing first-degree (36%) or second-degree (64%) obstruction at endoscopy. Overnight polysomnography, upper airway computed tomography and nasal endoscopy are useful tools for diagnosing obstructive sleep apnoea syndrome in mucopolysaccharidoses, and identifying the site and severity of airway obstruction.

Stereochemical control of DNA biosynthesis.

Stereochemical control of DNA biosynthesis was studied using several DNA-synthesizing complexes containing, in each case, a single substitution of a 2'-deoxy-D-nucleotide residue by an enantiomeric L-nucleotide residue in a DNA chain (either in the primer or in the template) as well as 2'-deoxy-L-ribonucleoside 5'-triphosphates (L-dNTPs) as substrates. Three template-dependent DNA polymerases were tested, Escherichia coli DNA polymerase I Klenow fragment, Thermus aquaticus DNA polymerase and avian myeloblastosis virus reverse transcriptase, as well as template-independent calf-thymus terminal deoxynucleotidyl transferase. Very stringent control of stereoselectivity was demonstrated for template-dependent DNA polymerases, whereas terminal deoxynucleotidyl transferase was less selective. DNA polymerase I and reverse transcriptase catalyzed formation of dinucleoside 5',5'-tetraphosphates when L-dTTP was used as substrate. Comparison between models of template-primer complexes, modified or not by a single L-nucleotide residue, revealed striking differences in their geometry.

A two B-Z junction containing DNA resolves into an all right-handed double-helix.

Natural and artificial oligonucleotides are capable of assuming many different conformations and functions. Here we present results of an NMR restrained molecular modelling study on the conformational preferences of the modified decanucleotide d((m)C1G2(m)C3G4C5(L)G6(L)(m)C7G8(m)C9G10) .d((m)C11G12(m)C13G14C15(L)G (L)16(m)C17-G18(m)C19G20 ) which contains L deoxynucleotides in its centre. This chimeric DNA was expected to form a right-left-right-handed B-type double-helix (BB*B) at low salt concentration. Actually, it matured into a fully right-handed double helix with its central C(L)pG(L) core forming a right-handed Z-DNA helix embedded in a B-DNA matrix (BZ*B). The interplay between base-base and base-sugar stackings within the core and its immediately adjacent residues was found to be critical in ensuring the stabilisation of the right-handed helix. The structure could serve as a model for the design of antisense oligonucleotides resistant to nucleases and capable of hybridising to natural DNAs and RNAs.

The effect of transfusion on pulmonary function in patients with thalassemia major.

Pulmonary involvement has been documented in thalassemia major (TM). We studied 12 patients with TM before and 24 hr after transfusion to evaluate the effect of transfusion on baseline lung function. Personal and family histories of respiratory illnesses were obtained by a questionnaire. Spirometry and carbon monoxide diffusion capacity (KCO) measurements were made. Blood gases (PO2 and SO2) were determined on arterialized samples. Baseline expiratory volumes and flows were within normal range in all patients. Transfusion resulted in a significant reduction of forced expiratory volume in 1 sec (FEV1) and forced expiratory flow between 25 and 75% vital capacity (FEF25-75%). In two subgroups of patients identified by the questionnaire, those with no history of airway disease had normal baseline flows and no posttransfusion changes; those with history of airway obstruction had lower pretransfusion flows and significantly decreased posttransfusion FEV1 and FEF25-75%. The mean pretransfusion KCO value of 80% predicted for the whole group, significantly increased after transfusion (P < 0.05). Blood gases also significantly increased after transfusion (P < 0.05). When tested for the spirometric response to albuterol, patients with a history of asthma had a slightly greater increase in FEV1 and FEF25-75% than those who had never had asthma. We conclude that in our small study group, transfusion resulted in improved gas exchange and lung perfusion. The effect on flow limitation evident in some patients could, in part, be related to a preexisting bronchial hyperreactivity. Accurate evaluation of pulmonary function and of bronchial reactivity is advisable for patients with TM.

Physical performance in patients with thalassemia before and after transfusion.

Patients with thalassemia who are on chronic transfusion programs have chronic ventilatory and cardiocirculatory abnormalities. We studied flow-volume curves, blood gas exchange, and cardiorespiratory responses to exercise in 12 patients with thalassemia major (TM) before and 24 hours after transfusions. Cardiorespiratory fitness was assessed with an exercise tolerance test on a cycle-ergometer. Ten healthy controls underwent the same protocol twice, first at baseline and then 24 hours later, without having had transfusions. We identified two subgroups of patients with a questionnaire: 1) those with no history of airway disease; and 2) those with a history of airway obstruction. Patients with no history of airway disease had normal baseline expiratory flows and no posttransfusion changes; those with a history of airway obstruction had lower pretransfusion expiratory flows rates and significantly decreased posttransfusion forced expiratory volume in 1 second (FEV1) and forced expiratory flow at 25-75% of forced vital capacity (FEV25-75%). As a group, TM patients had significantly lower pretransfusion cardiorespiratory function than controls; TM patients' maximum workload was 33% lower, maximum ventilation was 38% lower, maximum oxygen uptake was 25.7% lower, oxygen pulse was 28.6% lower, dyspnea index was 10.6% lower, and ventilatory equivalent for oxygen was 27.1% lower than in control subjects. Although cardiorespiratory responses to exercise improved in both subgroups after transfusion, patients with a history of airways obstruction had a significant posttransfusion increase in their dyspnea index (P = 0.05) and further increased their already abnormally high values of PETCO2 (43 mmHg). These results suggest that the transfusion worsened relative hypoventilation at the maximum workload only in the subgroup with a history of airway obstruction.

Investigating spike backpropagation induced Ca2+ influx in models of hippocampal and cortical pyramidal neurons.

We modeled the influx of calcium ions into dendrites following active backpropagation of spike trains in a dendritic tree, using compartmental models of anatomically reconstructed pyramidal cells in a GENESIS program. Basic facts of ion channel densities in pyramidal cells were taken into account. The time scale of the backpropagating spike train development was longer than in previous models. We also studied the relationship between intracellular calcium dynamics and membrane voltage. Comparisons were made between two pyramidal cell prototypes and in simplified model. Our results show that: (1) sodium and potassium channels are enough to explain regenerative backpropagating spike trains; (2) intracellular calcium concentration changes are consistent in the range of milliseconds to seconds; (3) the simulations support several experimental observations in both hippocampal and neocortical cells. No additional parameter search optimization was necessary. Compartmental models can be used for investigating the biology of neurons, and then simplified for constructing neural networks.

[Curative radiotherapy with hope of saving the breast in operable breast cancers 403 cases with 5-year survival]. / Radiothérapie curative à espérance conservatrice des cancers du sein opérables. 403 cas de 5 ans

Between 1960 and 1975, 1 078 operable mammary carcinomas were treated by caesium therapy with the objective of conserving the breast. The authors analyse the indications for and results of this treatment in the 403 cases which have had more than 5 years follow up (241 cases were irradiated as primary treatment, 162 after having a simple tumorectomy). For the whole group 92 mastectomies were ultimately carried out: in 30 of them no tumour was found in the operative specimen. The tumorectomy cases, restricted to stage 1 of the UICC classification (pre 1962) -- PRV 0 IGR yielded the best results: 86 per cent 5 yeat cures with 9 out of 10 women retaining both breasts. The primary irradiation cases, all types considered, gave results comparable with those for primary radical surgery: 58 per cent 5 year cures-but 2 out of 3 women retained both breasts. By itself caesium therapy is capable of eradicating tumour in breast and axilla in half of the cases. It really amounts to a "double chance strategy"--an attempt at cure if possible with avoidance of mastectomy, this being in reserve in the event of failure.

[Acute effects of propranolol and its association with nifedipine in aged patients with effort stable angina. Randomized double-blind crossover study, under placebo control]. / Effetti acuti del propranololo e sua associazione con nifedipina in pazienti anziani con angina stabile da sforzo. Studio a doppio cieco, randomizzato, cross-over, controllato con placebo.

Calcium-antagonist and B-blockers are effective in improving exercise tolerance in patients with effort angina. We studied the short effects of oral administration of nifedipine (10 mg) and propranolol (80 mg) alone and in combination in 15 elderly patients with chronic exertional angina pectoris in a double-blind, randomized, cross-over study. The 15 patients (13 men and 2 women, mean age 69 years) performed symptoms-limits bicycle exercise stress test 3 h after placebo or active substance administration. Maximal work load, exercise duration, real time to 1 mm ST segment depression were significantly increased and ST depression at peak exercise was significantly decreased by drug alone and in combination. Propranolol and nifedipine improved exercise duration in combination; however, a different response to the three pharmacologic interventions was found in patients treated with single drug. The improvement in exercises tolerance was associated with rate-pressure product values at peak exercise tolerance was associated with rate-pressure product values at peak exercise, unchanged after placebo and significantly reduced after both propranolol alone and in combination. After placebo all patients had exercise-induced angina, in 50% and in 40% after propranolol and the combination of the two drugs, respectively. In aging patients nifedipine and propranolol are effective in the treatment of effort angina and they are superior in patients who show poor response to mono therapy, although this combination will be conditioned by different patient sensibility to the three pharmacologic interventions and then therapeutic choice would be evaluated and verified individually.

[Mucinous adenocarcinoma. Unusual prostatic tumor]. / Adenocarcinoma mucinoso. Una tumoración prostática poco frecuente.

We report a case of mucinous adenocarcinoma of the prostate. A 80 years-old patient was diagnosed with a transrectal multiple biopsy. We comment on the special histological patterns of the tumor as well as the established criterion for an appropriate diagnosis.

[Multilocular cyst of the kidney: clinico-pathologic considerations]. / Quiste multilocular renal: consideraciones clínico-patológicas.

Multilocular Renal Cyst is a variety contained within the Spectrum of Renal Embryonic Tumors, presenting much confusion relating to its terminology, histology, clinical aspects, etc. We have carried out a review of this subject through bibliographical compilation of the cases published between 1976-86, and close analysis of the series thus far published. The diagnostic criteria described by Boggs and Kimmeslstiels in 1956, which classify this entity separate from other varieties of R.E.T. and similar ones. This pathological state can be seen in both children and adults, and it is characterized by its unusual appearance, clinical silent in the adults and in the child it appears as an abdominal mass. This pathology lacks specific diagnostic tests as well as the assistance rendered by clinical, radiological or ultrasound studies, it will depend on a correct preoperative diagnosis, an extremely difficult task to achieve, or on a diagnostic approximation geared to avoid in the child population the implementation of coadjuvant measures to surgery that will no doubt give rise to unwanted situations in the long run. The treatment of this pathology is strictly surgical and must be preceded by an extremely conservative approach. Tumorectomy or Partial Nephrectomy is curative and sufficient. From the anatomopathological study of the surgical sample, the correct diagnosis may be inferred.

[Breast cancer: prognostic factors. Apropos of 1000 conservative treatments]. / Cancer du sein: facteurs pronostiques. A propos de 1000 traitements conservateurs.

Prognosis was analyzed as a function of histologic grade, axillary gland spread and hormonal receptors in a consecutive series of 1000 patients with breast cancer (stages I and II) treated by conservative tumorectomy and axillary curettage, combined with radiotherapy, and followed up for between 3 and 12 years. The three factors analyzed are of major importance in that they constituted a veritable tumoral identity card. Grade I tumors, the absence of glandular spread and the presence of hormonal receptors are correlated with cancer of good prognosis, whereas grade III tumors, major axillary spread and absence of hormonal receptors are related to a poor prognosis. Their interactions are studied by comparing associations of good and poor prognostic factors, allowing determination of populations at low and high risk of therapeutic failure.