Recent Advances in the Treatment of Pulmonary Arterial Hypertension Associated with Connective Tissue Diseases.

Pulmonary hypertension (PH) is a severe vascular complication of connective tissue diseases (CTD). Patients with CTD may develop PH belonging to diverse groups: (1) pulmonary arterial hypertension (PAH), (2) PH due to left heart disease, (3) secondary PH due to lung disease and/or hypoxia and (4) chronic thromboembolic pulmonary hypertension (CTEPH). PAH most often develops in systemic scleroderma (SSc), mostly in its limited variant. PAH-CTD is a progressive disease characterized by poor prognosis. Therefore, early diagnosis should be established. A specific treatment for PAH-CTD is currently available and recommended: prostacyclin derivative (treprostinil, epoprostenol, iloprost, selexipag), nitric oxide and natriuretic pathway: stimulators of soluble guanylate cyclase (sGC: riociguat) and phosphodiesterase-five inhibitors (PDE5i: sildenafil, tadalafil), endothelin receptor antagonists (ERA: bosentan, macitentan, ambrisentan). Moreover, novel drugs, e.g., sotatercept, have been intensively investigated in clinical trials. We aim to review the literature on recent advances in the treatment strategy and prognosis of patients with PAH-CTD. In this manuscript, we discuss the mechanism of action of PAH-specific drugs and new agents and the latest research conducted on PAH-CTD patients.

Physiotherapeutic assessment and management of overactive bladder syndrome: a case report.

INTRODUCTION: Overactive Bladder Syndrome (OAB) has multiple treatment methods including pharmacotherapy, pelvic floor muscle training, electrostimulation, or surgery. One of the nonpharmacological treatment options is physiotherapy including pelvic floor muscle training. CASE DESCRIPTION: The patient was a 25 year-old woman who attended the urogynecological physiotherapy consulting room due to frequent sensations of bladder pressure. Manual inspection and ultrasound imaging was used by the physiotherapist in order to assess the function of pelvic and abominal structures. The patient reported pain symptoms during examination of several pelvic floor and abdominal muscles. The patient was judged eligible for urogynecological physiotherapeutic treatment. Manual therapy of the lumbopelvic hip complex, manual therapy per vaginum, manual therapy of the musculus piriformis, and therapy of the superficial back line myofascial meridian and the lateral line myofascial meridian were used. During the final session, the patient reported an improvement in relation to the symptoms presented, most notably no frequent feeling of bladder pressure. CONCLUSIONS: Treatment of OAB is often a multistage process involving application of different therapies by a multidisciplinary team. For this patient, physiotherapy assessment and intervention were an integral part of the conservative management of OAB.

Analyses of human vaccine-specific circulating and bone marrow-resident B cell populations reveal benefit of delayed vaccine booster dosing with blood-stage malaria antigens.

We have previously reported primary endpoints of a clinical trial testing two vaccine platforms for the delivery of Plasmodium vivax malaria DBPRII: viral vectors (ChAd63, MVA), and protein/adjuvant (PvDBPII with 50µg Matrix-M™ adjuvant). Delayed boosting was necessitated due to trial halts during the pandemic and provides an opportunity to investigate the impact of dosing regimens. Here, using flow cytometry - including agnostic definition of B cell populations with the clustering tool CITRUS - we report enhanced induction of DBPRII-specific plasma cell and memory B cell responses in protein/adjuvant versus viral vector vaccinees. Within protein/adjuvant groups, delayed boosting further improved B cell immunogenicity compared to a monthly boosting regimen. Consistent with this, delayed boosting also drove more durable anti-DBPRII serum IgG. In an independent vaccine clinical trial with the P. falciparum malaria RH5.1 protein/adjuvant (50µg Matrix-M™) vaccine candidate, we similarly observed enhanced circulating B cell responses in vaccinees receiving a delayed final booster. Notably, a higher frequency of vaccine-specific (putatively long-lived) plasma cells was detected in the bone marrow of these delayed boosting vaccinees by ELISPOT and correlated strongly with serum IgG. Finally, following controlled human malaria infection with P. vivax parasites in the DBPRII trial, in vivo growth inhibition was observed to correlate with DBPRII-specific B cell and serum IgG responses. In contrast, the CD4+ and CD8+ T cell responses were impacted by vaccine platform but not dosing regimen and did not correlate with in vivo growth inhibition in a challenge model. Taken together, our DBPRII and RH5 data suggest an opportunity for protein/adjuvant dosing regimen optimisation in the context of rational vaccine development against pathogens where protection is antibody-mediated.

Human lymphoid tissue sampling for vaccinology.

Long-lived plasma cells (LLPCs) - largely resident in the bone marrow - secrete antibody over months and years, thus maintaining serum antibody concentrations relevant for vaccine-mediated immunity. Little is known regarding factors that can modulate the induction of human LLPC responses in draining lymph node germinal centres, or those that maintain LLPCs in bone marrow niches following vaccination. Here, we review human and non-human primate vaccination studies which incorporate draining lymph node and/or bone marrow aspirate sampling. We emphasise the key contributions these samples can make to improve our understanding of LLPC immunology and guide rational vaccine development. Specifically, we highlight findings related to the impact of vaccine dosing regimens, adjuvant/vaccine platform selection, duration of germinal centre reactions in draining lymph nodes and relevance for timing of tissue sampling, and heterogeneity in bone marrow plasma cell populations. Much of this work has come from recent studies with SARS-CoV-2 vaccine candidates or, with respect to the non-human primate work, HIV vaccine development.

Use of Multiple Wharton Jelly Mesenchymal Stem Cell Transplants in Treatment of Incomplete Spinal Cord Injury: A Case Report.

Interruption of spinal cord continuity remains an incurable condition that leads to functional loss below the lesion level. Effective treatment to enable spinal cord regeneration is lacking, although cell therapy is an evolving opportunity. Therefore, the purpose of this study was to evaluate the safety and potential efficacy of multiple Wharton jelly mesenchymal stem cell transplants in a patient with a spinal cord injury. A patient with incomplete spinal cord interruption at the T11 to T12 vertebrae was enrolled in experimental therapy. The patient scored A/B on the ASIA scale (developed by the American Spinal Injury Association) with deep paraparesis and sphincter palsy. However, full ability to fix the patient's trunk upon admission was confirmed. Bilateral axonal damage of motor and sensory neural fibers of lower extremities was confirmed with electromyography and electroneurography. One year of standard therapy did not bring any positive results. The patient underwent 5 rounds of Wharton jelly mesenchymal stem cell transplants every 3 months (total treatment time of 18 months). There were no complications connected with therapy during the 18- month follow-up. Continuous neurological and quality of life improvements were seen after every transplant. The patient's ASIA score changed from A/B to C/D and from 112 to 231 points. The sensation level decreased from the T12 to L3 to L4 level. The patient regained bladder control and anal sensation. Muscle strength at the left lower extremity improved. The patient gained the ability to stand in a standing frame and walk with an orthosis. Neurophysiological examinations objectively confirmed the improvement. Magnetic resonance imaging demonstrated no changes in the spinal cord signal. The treatment demonstrated an objective improvement that could be used for patients with chronic thoracic incomplete spinal cord injury.

Characteristics of Injuries Sustained Under the Influence of Alcohol in a Group of Adolescents: Is it Possible to Establish a Typical Clinical Picture of an Underage Patient Who Suffered From an Injury Under the Influence of Alcohol?

OBJECTIVES: Fractures of the limbs and craniocerebral trauma are the most common injuries in children and adolescents. Their frequency ranges widely from 32% to 85% and is the main reason for hospitalization in pediatric population. The number of injuries sustained under the influence of alcohol is increasing although the data concerning that subject is limited and usually includes both adult and teenage patients. METHODS: A group of 111 adolescents (age, 9-18 years), hospitalized after traumatic brain injury with and without alcohol intoxication, was included in the study. We performed the assessment of the severity of the course of the multiorgan and craniocerebral injuries. The study was accepted by the Ethics Committee of the Jagiellonian University Medical College (no: KBET/8/B/2010). RESULTS: The injuries of upper limbs and head and their serious consequences were observed more often in the examined group. The differences of the degree of head and neck injuries measured in the Injury Severity Score between the groups were statistically significant, although the injuries within the examined group were less often serious. There was a negative correlation between the patients' condition according to the Glasgow Coma Scale and the concentration of alcohol in their blood. No link between the patients' assessment in the Injury Severity Score and concentration of alcohol in the blood was noticed. CONCLUSIONS: Traumatic brain injury under the influence of alcohol in adolescents differs from trauma in patients who had not drunk alcohol. Similar areas of injury result in a more severe course of illness in the examined group.

Epilepsy and cognitive deterioration as postoperative complications of the arachnoid cyst fenestration: Case report.

Objective: With the aim of contributing to the discussion on treatment of patients with arachnoid cysts (AC) and their neuropsychological functioning, we present the case of a patient who has undergone surgery of AC located in the left Sylvian fissure. Case description: The patient had no cognitive deficits and no seizures before the cyst's fenestration. After the procedure, however, occurrences of seizures have been observed. Along with the concomitant epileptic seizures, aphasia and serious memory problems also developed. The initial pharmacological treatment of the seizures brought about unsatisfactory results. The treatment was therefore modified a number of times and ultimately, seizures were brought under control to some extent. Despite the varied efforts at neuropsychological rehabilitation, cognitive impairment was still persistent up to a year after the surgery. Conclusions: 1) While referring patients with AC for surgery, one should always consider both the positive outcomes and the unintended and deleterious consequences. A cyst fenestration could in some cases lead to epilepsy and cause neuropsychological symptoms such as anomic aphasia and cognitive deterioration with memory function impairment. 2) Neurological patients, especially the ones qualified for surgery, should always undergo neuropsychological examination. The lack of data from presurgical neuropsychological examination may impact further treatment of neurosurgical patients.

The health-related quality of life in children with arachnoid cysts. Clinical predictors and parent-child perspectives.

BACKGROUND: In clinical practice, arachnoid cysts (AC) are usually detected by coincidence and are frequently considered as clinically mute. Even though an AC does not usually result in serious symptoms, the diagnosis itself can have a significant impact on the patients and their families, especially in terms of psychological functioning and quality of life. METHODS: Participants were 22 children diagnosed with AC and their parents. We analyzed patients' medical records and assessed them using the Stanford Binet Intelligence Scale, fifth edition. Additionally, both children and parents filled in the Polish version of the PedsQL™ 4.0 generic core module. RESULTS: The Health-RelatedQuality of Life (HRQOL) is not related to objective predictors such as radiological predictors and SB 5 results. However, there is a correlation between the HRQOL, and symptoms given in the interview. Secondly, parents assess the HRQOL of their children worse compared to the children's own ratings. Lastly, children with AC assess the HRQOL in a way that is similar to the assessment done by healthy children in the original study describing PedsQL™, whereas parents assess children's HRQOL in a way rather similar to the assessment done by parents of patients. CONCLUSIONS: The results show the impact of the disease's image and understanding on the HRQOL. Basing on our results we conclude the important role of psychological support for patients with AC. We furthermore conclude that parents of children with AC assess the HRQOL of children worse compared to the children's own ratings.

Cognitive characteristics of children treated for deformational plagiocephaly and parental perception of the therapy.

BACKGROUND: Deformational plagiocephaly (DP) is a common acquired skull deformity, with the highest incidence at the age of 4 months (19.7%). As it is considered benign, good cosmetic outcome is the primary aim of treatment, which includes either repositioning therapy (RT) with or without physiotherapy or molding helmet therapy (MHT). However, the issue of possible developmental delays in this group has been investigated. METHODS: Children aged 2-7 years previously treated with RT or MHT for DP were eligible for the study. Patients were examined by a psychologist using Stanford-Binet 5 Scale (SB5), while parents filled in a questionnaire, investigating their perception of the therapy and child's cognitive performance. RESULTS: Twenty-one patients were found to be eligible and agreed to participate in the study. Subgroups consisting of 11 RT (eight males; median age 4 years [range 2-7 years]) and 10 MHT (seven males; median age 4 years [range 2-6 years]) patients were analyzed. Mean and median SB5 scores in whole group were within normal range and no significant differences were found between them in RT and MHT groups. In MHT group, children with left-sided asymmetry scored significantly higher in working memory (WM). Overall parental satisfaction with therapy had no relation to SB5 scores in whole analyzed group, but in RT group a rate of 5 was more common among parents whose children scored better in visual-spatial processing (VSP, P=0.042). Therapy safety was more likely to be rated as 5 in patients who scored higher in QR (P=0.023) and WM (P=0.005); in RT group this relationship was found only in WM (P=0.011). CONCLUSIONS: Our results suggest that, in absence of medical conditions affecting cognitive performance, cognitive abilities of children aged 2-7 years treated for DP either by MHT or RT are undisturbed. Although majority of parents are satisfied with chosen therapy, those whose children have better cognitive performance are more likely to rate therapy higher.

Are arachnoid cysts actually clinically mute in relation to neuropsychological symptoms? Cognitive functioning in children with AC of middle and cranial fossa.

Aiming at being part of the discussion about the cognitive functioning of patients with arachnoid cysts (AC) and the value of neuropsychological testing in these patients, we present our study in which we investigated the cognitive functioning of 32 children with ACs of the middle cranial fossa. We compared the Stanford Binet 5 (SB 5) results obtained by the patients with the population mean values and analysed the relation between the patients' clinical details and the results of SB 5. The main conclusions of this research are: (1) In SB 5 tasks, the tested group performed worse than the population mean, which could be related to AC of the middle cranial fossa. Deficits concern especially visuospatial reasoning, quantitative reasoning, and knowledge. The obtained results indicate the coexistence of cognitive impairment and AC of the middle cranial fossa. (2) In patients with AC, neuroimaging information has only limited predictive ability regarding cognitive syndromes. (3) The complaints reported in the interview are not necessarily objectively reflected in the clinical assessment. Neuropsychological assessment should be part of the management of all patients with AC. (4) Cognitive deficits in patients with AC may become more pronounced with age. Accordingly, increasing school difficulties in these patients should be expected. In light of the above, there is a clear indication of the need for neuropsychological support and support in school functioning for patients with AC. (5) Neuropsychological control in patients with AC is crucial not only with regard to treatment decisions but primarily for monitoring school performance and providing these patients with adequate neuropsychological and psychological support.

Recurrent Urinary Tract Infection: A Mystery in Search of Better Model Systems.

Urinary tract infections (UTIs) are among the most common infectious diseases worldwide but are significantly understudied. Uropathogenic E. coli (UPEC) accounts for a significant proportion of UTI, but a large number of other species can infect the urinary tract, each of which will have unique host-pathogen interactions with the bladder environment. Given the substantial economic burden of UTI and its increasing antibiotic resistance, there is an urgent need to better understand UTI pathophysiology - especially its tendency to relapse and recur. Most models developed to date use murine infection; few human-relevant models exist. Of these, the majority of in vitro UTI models have utilized cells in static culture, but UTI needs to be studied in the context of the unique aspects of the bladder's biophysical environment (e.g., tissue architecture, urine, fluid flow, and stretch). In this review, we summarize the complexities of recurrent UTI, critically assess current infection models and discuss potential improvements. More advanced human cell-based in vitro models have the potential to enable a better understanding of the etiology of UTI disease and to provide a complementary platform alongside animals for drug screening and the search for better treatments.

Cognitive Impairment in Children with Arachnoid Cyst of Sylvian Fissure: Does it Justify the Neurosurgical Treatment?

This report discusses the relationship between arachnoid cysts (ACs) and cognitive deficits, and we ask if cognitive impairments could justify neurosurgical treatment. In clinical practice, only AC patients with symptoms of intracranial hypertension or focal neurological deficits are referred to surgery. Occasionally, one might assume that nonspecific problems such as impairment of learning, speech, or cognitive functions are caused by an AC and can be improved by surgery. We describe three patients, in which surgery was indicated on the basis of clinical symptoms such as headaches and the size of the cysts. A neuropsychological examination before AC surgery revealed reduced cognitive potential, and the same examination repeated after surgery showed improvement. We have not found any other reason for this change, except for the decompression of the AC.

Cognitive disorders in a patient with an arachnoid cyst of the sylvian fissure and improvement after surgical treatment: Case description.

Arachnoid cysts cause a wide spectrum of clinical symptoms. Often it is difficult to clearly establish the relation between the presence of an arachnoid cyst and problems reported by the patient, which may, although not necessarily, be due to chronically elevated intracranial pressure. In recent years, increasing attention is paid to cognitive disorders accompanying arachnoid cysts, such as memory disorders, attention disorders, or language function disorders. This article presents a case of an 11-year-old patient, treated at the University Children's Hospital in Cracow for an arachnoid cyst, located in the left middle cranial fossa. This analysis is focused on the description of cognitive and intellectual deficits of the child, as well as the discussion on their connection with the arachnoid cyst. Prior to the neurosurgical procedure, the boy presented significant deficits in cognitive functions, especially mnestic and attention functions and, also, a quite low level of intellectual functioning. Neuropsychological examination performed after the procedure indicated a significant improvement of cognitive functioning for all the functions, as well as a higher level of intellectual functioning. This analysis attempts to answer whether and to what extent the child still suffers from cognitive deficits from the organic lesions.

Engineering Candida albicans glucosamine-6-phosphate synthase for efficient enzyme purification.

Rationally designed muteins of Candida albicans glucosamine-6-phosphate synthase, an enzyme known as a promising target for antifungal chemotherapy, were constructed, overexpressed in Escherichia coli and purified to near homogeneity. To facilitate and to optimize the purification of the enzyme, three recombinant versions containing internal oligoHis fragments were constructed: (i) by substituting residues 343-348 of the interdomain undecapeptide linker with hexaHis, (ii) by replacing solvent-exposed residues 655-660 of the isomerase domain with hexaHis, and (iii) by replacing amino acids at positions 568 and 569 with His residues to generate the three-dimensional hexaHis microdomain in the enzyme quaternary structure. The resulting constructs were effectively purified to near homogeneity by rapid, one-step immobilized metal-ion affinity chromatography and demonstrated activity and catalytic properties comparable with that of the wild-type enzyme. The construct containing the 655-660 hexaHis insert was found to be a homodimeric protein, which is the first reported example of such quaternary structure of glucosamine-6-phosphate synthase of eukaryotic origin.