The HELLP syndrome: clinical issues and surgical management. A Case Experience.

AIM: This study aims to challenge the current know-how in patients with spontaneous rupture of a liver hematoma, to differentiate amongst patients requiring such specific surgical therapy and avoiding mistakes during surgical operations, in order to terminate pregnancy with beneficial effects on the mother and fetus. MATERIALS AND METHODS: In a emergency scenario we admitted a 37-year-old woman at 35+4 weeks of gestation for emergency cesarean section after the onset of right hypochondrium pain. A diagnosis of hemoperitoneum and severe preeclampsia with liver and splenic bleeding was done and managed with packing of hepatic and splenic hematomas and according to her haemo-dynamic clinical conditions, done in different time. RESULTS: A diagnosis of hemoperitoneum and severe pre-eclampsia with liver and splenic bleeding was done and managed it with 3 xypho-pubic-laparatomy in different time with haemostatic packing. DISCUSSION: In this case report, the patient underwent an emergency caesarean section and was managed with packing of hepatic and splenic hematomas and according to her haemodynamic clinical conditions was operated in different time. The choice of laparotomy and hepatic packing has proved to be a viable option in patients with unstable vital signs and is feasible even in limited resource settings. CONCLUSION: Short interval between diagnosis and management may enhance the feto-maternal survival rate and prevent further morbidity or mortality. The choice of laparotomy and hepatic packing has proved to be a viable option in patients with unstable vital signs and is feasible even in limited resource settings. KEY WORDS: HELLP syndrome, Liver hematoma rupture, Packing.

Total Knee Arthroplasty in Haemophilia: Long-Term Results and Survival Rate of a Modern Knee Implant with an Oxidized Zirconium Femoral Component.

(1) Background: Total Knee Arthroplasty (TKA) in patient with haemophilia (PWH) has usually been performed with the use of cobalt-chrome femoral and titanium tibial components, coupled with standard polyethylene (PE) inserts. The aim of this retrospective study was to evaluate the long-term outcomes and survival rates of TKA in a series of consecutive PWH affected by severe knee arthropathy at a single institution. (2) Methods: We followed 65 patients undergoing 91 TKA, implanted using the same implant, characterized by an oxidized zirconium femoral component, coupled with a titanium tibial component, and a highly crosslinked PE. At 1, 6, and 12 months; then every year for 5 years; and finally, every other 3 years, all patients were scored for pain (VAS), function (HJHS; KSS), ROM, and radiographic changes. Kaplan-Meier survivorship curves were used to calculate the implant survival rates. (3) Results: The mean follow-up was 12.3 years (4.2-20.6). All clinical and functional scores improved significantly from preoperatively to the latest follow-up (VAS: from 6.9 to 1.3; HJHS: from 13.4 to 1.9; KSS: from 19.4 to 79; ROM: from 42.4° to 83.6°). The overall survivorship of the implants was 97.5% at the latest follow-up. (4) Conclusions: The present series showed a high survival rate of specific implants potentially linked to the choice of an oxidized zirconium coupled with a highly crosslinked PE. We promote the use of modern implants in these patients in order to ensure long-lasting positive outcomes.

Cannabis-Based Products in a Neurological Setting: A Clinical and Pharmacokinetic Survey.

Background and Aim: Limited data are available in clinical settings on the pharmacokinetics of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). We investigated the use of cannabis-based products in neurological practice, monitoring patients' steady-state cannabinoids (CBs) plasma concentrations matched with different preparations. Methods: This was a prospective, single-center, observational study. Patients underwent venous blood withdrawal before the CBs' morning dose and then 2.5 h post-dosing. Spasticity or pain were patient self-assessed by the Numeric Rating Scale (NRS) before the morning CB's administration and 2.5 h post-dosing. Results: Thirty-three patients were enrolled. Main indications for CBs were spasticity and chronic pain. Sixteen patients were treated with oromucosal spray formulation Sativex® and 17 with oil-based solutions. Both CBs trough plasma concentrations were ≤ limit of detection (0.1 ng/ml) in 45% of patients. Intrasubject CB's plasma levels significantly increased over baseline values in patients treated with Bediol® oil (p < 0.05) and Sativex® (p < 0.01). Post-dosing CB's bioavailability did not significantly differ between oral oil and oromucosal spray. NRS scores decreased (p < 0.01), matching the increase (p < 0.01) in CB's plasma concentrations. Conclusion: This is the first study investigating CB's plasma concentrations of oral and oromucosal preparations in real-world neurological practice. Findings of similar bioavailability for both CBD and THC after galenic oil compared with oromucosal spray dosing may be clinically relevant and deserve additional research in larger cohorts.

A Rapid and Simple UHPLC-MS/MS Method for Quantification of Plasma Globotriaosylsphingosine (lyso-Gb3).

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by α-galactosidase A gene (GLA) mutations, resulting in loss of activity of the lysosomal hydrolase, α-galactosidase A (α-Gal A). As a result, the main glycosphingolipid substrates, globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3), accumulate in plasma, urine, and tissues. Here, we propose a simple, fast, and sensitive method for plasma quantification of lyso-Gb3, the most promising secondary screening target for FD. Assisted protein precipitation with methanol using Phree cartridges was performed as sample pre-treatment and plasma concentrations were measured using UHPLC-MS/MS operating in MRM positive electrospray ionization. Method validation provided excellent results for the whole calibration range (0.25-100 ng/mL). Intra-assay and inter-assay accuracy and precision (CV%) were calculated as <10%. The method was successfully applied to 55 plasma samples obtained from 34 patients with FD, 5 individuals carrying non-relevant polymorphisms of the GLA gene, and 16 healthy controls. Plasma lyso-Gb3 concentrations were larger in both male and female FD groups compared to healthy subjects (p < 0.001). Normal levels of plasma lyso-Gb3 were observed for patients carrying non-relevant mutations of the GLA gene compared to the control group (p = 0.141). Dropping the lower limit of quantification (LLOQ) to 0.25 ng/mL allowed us to set the optimal plasma lyso-Gb3 cut-off value between FD patients and healthy controls at 0.6 ng/mL, with a sensitivity of 97.1%, specificity of 100%, and accuracy of 0.998 expressed by the area under the ROC curve (C.I. 0.992 to 1.000, p-value < 0.001). Based on the results obtained, this method can be a reliable tool for early phenotypic assignment, assessing diagnoses in patients with borderline GalA activity, and confirming non-relevant mutations of the GLA gene.

Cerebrospinal Fluid Concentrations of Nimodipine Correlate With Long-term Outcome in Aneurysmal Subarachnoid Hemorrhage: Pilot Study.

OBJECTIVES: The aim was to evaluate plasma and cerebrospinal fluid (CSF) nimodipine concentrations in patients with aneurysmal subarachnoid hemorrhage and their correlation with clinical outcome. METHODS: Nimodipine infusion was started at 1 mg/h and increased up to 2 mg/h and continued up to 21 days in surviving patients. Arterial and CSF samples were collected at least after 24 hours of stable nimodipine dosing. Delayed cerebral ischemia and vasospasm were documented by new neurological deficits and neuroimaging. The clinical outcome was assessed at 9 months by the modified Rankin scale. RESULTS: Twenty-three patients were enrolled. Nimodipine dose was 13 to 38 µg/kg per hour. Nimodipine arterial and CSF concentrations were 24.9 to 71.8 ng/mL and 37 to 530 pg/mL, respectively. Dose did not correlate with arterial or CSF concentrations. Arterial concentrations did not correlate with corresponding CSF concentrations. Doses and arterial concentrations did not correlate with the clinical outcome and were not associated with the occurrence of delayed cerebral ischemia. However, patients with no significant disability after 9 months of hemorrhage showed significantly higher CSF nimodipine concentrations (P = 0.015) and CSF-to-plasma ratios (P = 0.011) compared with patients who showed some degree of disability or who died. CONCLUSIONS: Cerebrospinal fluid nimodipine concentrations measured during hospital drug infusion showed a correlation with long-term clinical outcome in patients with aneurysmal subarachnoid hemorrhage. These very preliminary data suggest that CSF concentrations monitoring may have some value in managing these patients.

Clinical pharmacokinetics of pramipexole, ropinirole and rotigotine in patients with Parkinson's disease.

INTRODUCTION: Pramipexole (PRA), ropinirole (ROP) and rotigotine (ROT) are non-ergoline dopaminergic agonists (DAs) used to treat Parkinson's disease (PD). Clinical pharmacokinetics of DAs is poorly characterized in PD. The main purpose of our study was to investigate the effect of dose, age and sex on steady-state plasma concentrations of DAs in real life PD patients on chronic DAs therapy. METHODS: The study was single center, open and prospective. Blood samples for measurement of DAs plasma concentrations were drawn in the morning, at a median 18-h distance from the last DA dose. RESULTS: Ninety-one patients treated with PRA, 50 with ROP and 37 with ROT were enrolled in the study. Plasma concentration of DAs significantly correlated with weight-adjusted daily dose in all subgroups, although at a given dose, matched plasma concentrations highly varied among patients. Median PRA plasma concentration-to-daily dose ratio (C/D) [(ng/mL)/(mg/kg/d)] was 68% higher in patients >65 years than ≤65 years (158 vs 94, p < 0.001), while was not affected by age in ROP and ROT subgroups. No sex-mediated differences in C/D ratios were observed in any group. CONCLUSION: These are the first observations on DAs pharmacokinetics in PD patients' everyday clinical practice. Of relevance, patients over 65yrs may require about one third of PRA dose compared to under 65yrs to achieve the same plasma concentration. Due to the high intersubject variability in plasma concentrations at the same dosage, we speculate that monitoring of plasma DAs might be helpful in the individualization of treatment in selected patients.

Tetrahydrocannabinol/Cannabidiol Oromucosal Spray in Patients With Multiple Sclerosis: A Pilot Study on the Plasma Concentration-Effect Relationship.

OBJECTIVES: We aimed to assess the potential relationship between intrasubject 9-tetrahydrocannabinol/cannabidiol (THC/CBD) oromucosal spray plasma profiles and clinical effects elicited by subacute dosing in chronically treated patients with multiple sclerosis (MS). METHODS: The study design was pilot, single center, open, and prospective. The patients were challenged with a morning test dose of 2 THC/CBD sprays at a 15-minute interval. Venous blood samples were collected before the first spray administration and every 30 minutes after the second spray, until 240 minutes postdosing. Patients rated their spasticity by the Numerical Rating Scale (NRS) simultaneously with blood drawings. Postural and motor tests were performed before the first spray and 90 and 180 minutes thereafter. RESULTS: Twelve patients were recruited. Peak plasma concentrations of THC/CBD largely varied among patients, from 0.60 to 13.29 ng/mL for THC and 0.55 to 11.93 ng/mL for CBD. Time to peak plasma concentrations ranged from 150 to 240 minutes for THC and 90 to 240 minutes for CBD. Patients' NRS serial scores decreased after dosing, from a median value of 6 to 3.5 (P < 0.001). A significant inverse correlation was observed between median intrasubject repeated NRS scores and corresponding median values of both THC (P < 0.01) and CBD (P < 0.002) plasma concentrations. No significant effect of cannabinoids dosing could be appreciated according to posturographic and motor tests. CONCLUSIONS: Our kinetic dynamic findings from THC/CBD oromucosal spray are the first obtained in real MS patients. Although preliminary, they suggest that subacute dosing might elicit a subjective clinically significant effect on MS-related spasticity, paralleling cannabinoids measurable plasma concentrations.

The DnaE polymerase from Deinococcus radiodurans features RecA-dependent DNA polymerase activity.

We report in the present study on the catalytic properties of the Deinococcus radiodurans DNA polymerase III α subunit (αDr). The αDr enzyme was overexpressed in Escherichia coli, both in soluble form and as inclusion bodies. When purified from soluble protein extracts, αDr was found to be tightly associated with E. coli RNA polymerase, from which αDr could not be dissociated. On the contrary, when refolded from inclusion bodies, αDr was devoid of E. coli RNA polymerase and was purified to homogeneity. When assayed with different DNA substrates, αDr featured slower DNA extension rates when compared with the corresponding enzyme from E. coli (E. coli DNA Pol III, αEc), unless under high ionic strength conditions or in the presence of manganese. Further assays were performed using a ssDNA and a dsDNA, whose recombination yields a DNA substrate. Surprisingly, αDr was found to be incapable of recombination-dependent DNA polymerase activity, whereas αEc was competent in this action. However, in the presence of the RecA recombinase, αDr was able to efficiently extend the DNA substrate produced by recombination. Upon comparing the rates of RecA-dependent and RecA-independent DNA polymerase activities, we detected a significant activation of αDr by the recombinase. Conversely, the activity of αEc was found maximal under non-recombination conditions. Overall, our observations indicate a sharp contrast between the catalytic actions of αDr and αEc, with αDr more performing under recombination conditions, and αEc preferring DNA substrates whose extension does not require recombination events.

Simultaneous ternary extension of DNA catalyzed by a trimeric replicase assembled in vivo.

According to current models, dimeric DNA Polymerases coordinate the replication of DNA leading and lagging strands. However, it was recently shown that trimeric DNA Polymerases, assembled in vitro, replicate the lagging strand more efficiently than dimeric replicases. Here we show that the τ, α, ε, and θ subunits of Escherichia coli DNA Polymerase III can be assembled in vivo, yielding the trimeric τ3α3ε3θ3 complex. Further, we propose a molecular model of this complex, whose catalytic action was investigated using model DNA substrates. Our observations indicate that trimeric DNA replicases reduce the gap between leading and lagging strand synthesis.

Bronchoscopic lung-volume reduction with one-way valves in patients with heterogenous emphysema.

BACKGROUND: We evaluated the feasibility and short-term functional outcome after bronchoscopic lung-volume reduction performed with one-way valves in patients with severe heterogeneous emphysema. METHODS: Thirteen patients entered this pilot study. Endobronchial one-way valves were placed in the segmental bronchi supplying the most hyperinflated parts of the emphysematous lungs to allow lung deflation, reduce lung volume, and alleviate symptoms. The valves and delivery catheter were inserted under intravenous anesthesia and spontaneous assisted ventilation, with visual control through a flexible bronchoscope. We performed unilateral bronchoscopic lung-volume reduction in 11 patients and staged bilateral procedures in 2. Preoperative median forced expiratory volume in 1 second (FEV1) was 0.75 L/s (22%), residual volume was 5.3 L (233%), total lung capacity, 7.9 L (123%); intrathoracic gas volume, 6.5 L (176%); and 6-minute walk test, 223 meters. All patients required supplemental oxygen at rest (1.4 L/min). The median preoperative Medical Research Council (MRC) scale dyspnea score was 4. RESULTS: Six complications occurred in 3 patients: two bilateral and one contralateral pneumothorax, one pneumonia, and two episodes of bronchospasm. Functional results at 1 and 3 months showed a significant improvement in FEV1, residual volume, and 6-minute walk test; 43% of the patients were able to completely stop supplemental oxygen. The posttreatment MRC median dyspnea score at 1 and 3 months was 2. Bronchoscopic follow up at 1 and 3 months showed that the valves were correctly in place with no granulation. CONCLUSIONS: Bronchoscopic lung-volume reduction with one-way valves can be performed with acceptable short-term safety and worthwhile functional benefits.

[Relationship between the obstructive sleep apnea syndrome and internal medicine]. / Correlazione tra la sindrome delle apnee notturne di tipo ostruttivo e la medicina interna.

Twelve to twenty-five percent of human population suffer from sleep disorders and sleep-related breathing disorders have a frequency of 5-10%. The association between sleep-related breathing disorders and several diseases, mainly cardiovascular and dysmetabolic, is well known. The aim of this study was to assess the prevalence of this association in a group of 620 patients, aged between 18 and 78 years and referred to the Laboratory of Respiratory Pathophysiology of the Umberto I Hospital of Rome. All patients had a clinical history of a sleep-related breathing disorder and answered a specific questionnaire. One-hundred-and-thirty-seven patients (120 males and 17 females, mean age 64 years), whose questionnaire was suggestive of a sleep-related breathing disorder, underwent clinical assessment including blood tests, lung function tests, blood-gas analysis, ECG and nocturnal polysomnography, either as in- or as out-patients. The main associated pathologies were: arterial hypertension (54.7%), chronic obstructive pulmonary disease (17.9%), obesity (63.1%), dyslipidemia (41%), type 2 diabetes mellitus (6.3%), gastroesophageal reflux (27.3%) and cardiac arrhythmias (4.2%); 95 patients with obstructive sleep apnea syndrome were treated, on the basis of the polysomnography outcomes and according to the Italian Association of Sleep Medicine Guidelines, either with preventive strategies for risk factor reduction, or with medical (positive pressure ventilation, oxygen, assessment of the best drug medication) and/or ear, nose end throat surgical therapies. In most patients, the improvement in the sleep-related breathing disorder was associated with an improvement in their systemic pathology, in particular cardiovascular disease, suggesting the need of a deeper consideration and comprehension of nocturnal apneas.