Idiopathic Patients Research Articles

New Insights on Sperm Function in Male Infertility of Unknown Origin: A Multimodal Approach.

The global trend of rising (male) infertility is concerning, and the unidentifiable causes in half of the cases, the so-called unknown origin male infertility (UOMI), demands a better understanding and assessment of both external/internal factors and mechanisms potentially involved. In this work, it was our aim to obtain new insight on UOMI, specifically on idiopathic (ID) and Unexplained male infertility (UMI), relying on a detailed evaluation of the male gamete, including functional, metabolic and proteomic aspects. For this purpose, 1114 semen samples, from males in couples seeking infertility treatment, were collected at the Reproductive Medicine Unit from the Centro Hospitalar e Universitário de Coimbra (CHUC), from July 2018-July 2022. Based on the couples' clinical data, seminal/hormonal analysis, and strict eligibility criteria, samples were categorized in 3 groups, control (CTRL), ID and UMI. Lifestyle factors and anxiety/depression symptoms were assessed via survey. Sperm samples were evaluated functionally, mitochondrially and using proteomics. The results of Assisted Reproduction Techniques were assessed whenever available. According to our results, ID patients presented the worst sperm functional profile, while UMI patients were similar to controls. The proteomic analysis revealed 145 differentially expressed proteins, 8 of which were specifically altered in ID and UMI samples. Acrosin (ACRO) and sperm acrosome membrane-associated protein 4 (SACA4) were downregulated in ID patients while laminin subunit beta-2 (LAMB2), mannose 6-phosphate isomerase (MPI), ATP-dependent 6-phosphofructokinase liver type (PFKAL), STAR domain-containing protein 10 (STA10), serotransferrin (TRFE) and exportin-2 (XPO2) were downregulated in UMI patients. Using random forest analysis, SACA4 and LAMB2 were identified as the sperm proteins with a higher chance of distinguishing ID and UMI patients, and their function and expression variation were in accordance with the functional results. No alterations were observed in terms of lifestyle and psychological factors among the 3 groups. These findings obtained in an experimental setting based on 3 well-defined groups of subjects, might help to validate new biomarkers for unknown origin male infertility (ID and UMI) that, in the future, can be used to improve diagnostics and treatments.

Peripheral Blood T Cells of Patients with IPAH Have a Reduced Cytokine-Producing Capacity.

Pulmonary arterial hypertension (PAH) is rare disease that is categorized as idiopathic (IPAH) when no underlying cause can be identified. Lungs of most patients with IPAH contain increased numbers of T cells and dendritic cells (DCs), suggesting involvement of the immune system in its pathophysiology. However, our knowledge on circulating immune cells in IPAH is rather limited. We used flow cytometry to characterize peripheral blood DCs and T cells in treatment-naive IPAH patients, compared with connective-tissue disease-PAH (CTD-PAH) patients and healthy controls (HCs). At diagnosis, T-helper (Th) cells of IPAH patients were less capable of producing TNFα, IFNγ, IL-4 and IL-17 compared to HCs. IPAH patients showed a decreased frequency of Th2 cells and significantly enhanced expression of the CTLA4 checkpoint molecule in naive CD4+ T cells and both naive and memory CD8+ T cells. Frequencies and surface marker expression of circulating DCs and monocytes were essentially comparable between IPAH patients and HCs. Principal component analysis (PCA) separated IPAH patients—but not CTD-PAH patients—from HCs, based on T-cell cytokine profiles. At 1-year follow-up, the frequencies of IL-17+ production by memory CD4+ T cells were increased in IPAH patients and accompanied by increased proportions of Th17 and Tc17 cells, as well as decreased CTLA4 expression. Treatment-naive IPAH patients displayed a unique T-cell phenotype that was different from CTD-PAH patients and was characterized by reduced cytokine-producing capacity. These findings point to involvement of adaptive immune responses in IPAH, which may have an implication for the development of therapeutic interventions.

Pulmonary arterial hypertension and atrial arrhythmias: incidence, risk factors, and clinical impact.

Atrial arrhythmia (AA) occurrence in pulmonary arterial hypertension (PAH) may determine clinical deterioration and affect prognosis. In this study we assessed AA incidence in idiopathic (IPAH) and systemic sclerosis related PAH (SSc-PAH) and evaluated risk factors, management, and impact on mortality. We collected baseline data from consecutive IPAH or SSc-PAH patients prospectively enrolled in the Johns Hopkins Pulmonary Hypertension Registry between January 2000 and July 2016. During follow-up AA onset, treatment, and outcome were recorded. Among 317 patients (201 SSc-PAH, 116 IPAH), 42 developed AA (19 atrial fibrillation, 10 flutter-fibrillation, 9 atrial flutter, and 4 atrial ectopic tachycardia) with a 13.2% cumulative incidence. Most events were associated with hospitalization (90.5%). Electrical or pharmacological cardioversion was attempted in most cases. Patients with AA had higher right atrial pressure, pulmonary wedge pressure (P < 0.005), NT-proBNP (P < 0.05), and thyroid disease prevalence (P < 0.005). Higher mortality was observed in patients with AA, though not statistically significant (LogRank P = 0.323). Similar long-term mortality between IPAH with AA and SSc-PAH without AA was observed (LogRank P = 0.098). SSc-PAH with AA had the worst prognosis. In PAH patients AA occurrence is a matter of significant concern. Therapeutic strategies aimed at restoring sinus rhythm may represent an important goal.

Efficacy of Gastric Electrical Stimulation for Gastroparesis: US/European Comparison.

BackgroundGastric electrical stimulation (GES) is used in both the US and Europe, but little research has investigated the demographics of gastroparesis patients receiving GES by geographic location.MethodsWe compared data from 380 patients, 296 female and 84 males, mean age 42 years, 246 idiopathic (ID), 107 diabetic (DM), and 27 post-surgical (PS). The statistical significance was calculated by Chi-square test and a P-value obtained for ID, DM, and PS. The statistical significance was calculated by Fischer exact test and a P-value obtained comparing male vs. female.ResultsEuropean centers had 61 GES patients compared to 319 from the US. In Europe, 100% of patients had gastric emptying test (GET) values available; in the US, it was 75% of patients. European centers had more DM patients (59%) than the US (22%), and a smaller proportion of ID patients (25%) than the US (72%). There was a statistical difference between the causes of gastroparesis in the patients receiving GES (P-value < 0.00001). There was also significant difference in the gender of the patients receiving GES, with a greater proportion of women in the US (P value = 0.0023).ConclusionsComparing GES in US vs. Europe demonstrated significant differences in gastroparesis demographics and percentage of patients with GET data. After analyzing the previously discussed results and reviewing recent updates in evidence-based medicine guidelines, the discrepancy and variance in patient populations in the US and Europe emphasizes the need for a database that allows better analysis and treatment of gastroparesis patients worldwide including stimulation therapies.

Laparoscopic treatment of gastroparesis: a single center experience

BackgroundGastroparesis (GP) is a chronic disorder of gastric motility with delayed gastric emptying. Gastric electrical stimulator (GES) implantation and Roux-en-Y gastric bypass (RYGB) are surgical options for medically refractory GP. ObjectiveEvaluate operational outcomes and symptom improvement of patients with diabetic (DM) and idiopathic (IP) GP. SettingUniversity Hospital, United States. MethodsA retrospective chart review was performed of all patients who underwent surgical treatment of GP from February 2003 to December 2014. Subgroup analysis was performed based on etiology of GP (DM versus IP) and procedure received (GES versus RYGB). Postoperative outcomes and postoperative symptom improvements were compared between groups. ResultsOf 93 patients, 47 (50.5%) had IP and 46 (49.5%) had DM. The majority underwent GES implantation (83.8%, n = 78), and 15 patients (16%) underwent RYGB. There were significant differences in hospital stay (2 versus 3 days) and reoperation rate (30% versus 7%) between IP and DM. Operation time, complication rate, and 30-day readmission rate were similar in both groups. DM patients significantly improved GP-related complaints compared with preoperatively. IP patients also improved nausea and vomiting and had no change in abdominal pain between pre- and postoperative period. GES showed significant improvement of nausea, vomiting, and abdominal pain. RYGB showed improvement of nausea, but not vomiting or abdominal pain. ConclusionsSurgery is a feasible intervention for GP for both DM and IP patients; however, based on the data presented in this manuscript and the current literature, the use of gastric bypass as an effective treatment modality for patients with intractable GP remains highly controversial. Care must be taken for IP patients in the postoperative period due to high incidence of reoperation. Although both procedures offer some degree of symptomatic improvement, GES seems to provide improvement of more GP symptoms. However, there is no significant difference in the need for postoperative medications regardless of the procedure used.

Real-world, long-term survival of incident patients with pulmonary arterial hypertension

BackgroundPulmonary arterial hypertension (PAH) is a progressive, fatal disease. Long-term outcomes data are scarce in Portugal. We aimed to estimate survival of newly diagnosed PAH at a Portuguese referral center in the modern management era. MethodsBetween January 2009 and November 2015 all incident PAH cases were consecutively enrolled in a prospective cohort study. Sixty-five patients were followed up for a median of 3.1 [interquartile range 1.7–5.4] years. Kaplan–Meier survival analysis was used to estimate 1-, 3-, and 5-year survival and to compare it with a historical PAH survival estimated from the NIH cohort. ResultsMean age was 48±19 years with female preponderance (68%). The most common PAH subgroup was congenital heart disease (PAH-CHD) (n=31; 48%), followed by connective tissue disease (PAH-CTD) (n=16; 25%), idiopathic (IPAH) (n=8; 12%) and hereditary (HPAP) (n=1; 1.5%). BNP values (hazard ratio [HR] 2.07; 95%CI 1.34–3.22; P=0.001) and male gender [HR 4.34 (1.44–13.09); P=0.009] were predictors of death. Survival rates at 1-, 3- and 5-years were 95%, 77% and 71%. Survival was not statistically different between PAH etiologies (Log-rank P=0.7). However, PAH-CHD was associated with a decreased risk of the combined endpoint of all-cause mortality and admission for decompensated heart failure [HR 0.36 (0.15–0.85); P=0.02]. We found a non-significant numerically higher survival of incident IPAH, HPAH and DPAH patients in comparison with the historical NIH cohort. ConclusionsIn this cohort of incident PAH patients, PAH-CHD patients had better overall prognosis. Higher BNP values and male gender were associated with higher mortality.

Analysis of the reliability of surgeons' ability to differentiate between idiopathic and degenerative spinal deformity in adults radiologically. What descriptive parameters help them decide?

Adult spinal deformity (ASD) may be classified as idiopathic (ID) or degenerative (DD) (or other) based on classifier's perception, the reliability of and factors inherent to which remain unknown. The aim of this study is to evaluate the inter- and intra-observer reliability of surgeons' perception in differentiating ID from DD and to identify the determinants of this differentiation. From a multicentric prospective database of ASD, 179 patients were identified with the diagnosis of ID (n=103) or DD (n=76); without previous surgery; and a lumbar coronal curve larger than 20°. Standing antero-posterior and lateral X-rays of these patients were sent to five experienced spine surgeons to be identified as DD or ID (or other); followed by a second round after reshuffling. Weighted kappa statistics were used, the strength of agreement for the kappa coefficient was considered as; 0.81-1=almost perfect, 0.61-0.8=substantial, 0.41-0.60=moderate, 0.21-0.40=fair, 0.01-0.20=slight, and≤0=poor. Patients were then stratified based on the number of agreements on a total of 10 rounds as excellent (10 out of 10), good (more than 7 out of 10) and fair/poor (7 and less). These excellent and good agreements were further compared for additional radiological parameters. Agreement levels were moderate to substantial for intra but mostly fair for inter-observer comparisons. For ID patients, there were 42 cases with excellent and 38 with very good agreement whereas for DD, there were no excellent and only 17 cases with very good agreement. Upon comparison of these (ID vs DD for at least very good cases), it was seen that they were different for some coronal parameters such as lumbar Cobb angle (larger in ID, p<0.001), central sacral vertical line (CSVL) modifier (C more common in ID, p=0.007) and presence of rotatory subluxation (less common in DD, p=0.017), but very different for sagittal parameters (lumbar lordosis, sagittal vertical axis, T2 sagittal tilt, pelvic tilt, sacral slope, and global tilt; increased sagittal imbalance in DD, all p≤0.001). Surgeons in this study demonstrated reasonable (moderate to substantial) intra-observer agreement, but only fair agreement amongst them. Alarming as it may appear, we should be cautious in interpreting these results based on only radiology and no clinical information. In patients with good agreement, the most consistent radiologic determinant of degenerative ASD appeared to be the presence of sagittal imbalance.

Treatment of Pulmonary Arterial Hypertension: Great Expectations!

> “Take nothing on its looks; take everything on evidence. There’s no better rule.” > > — Charles Dickens, Great Expectations Pulmonary arterial hypertension (PAH) is a serious, progressive, often fatal condition characterized by increased pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR)1,2. Patients with PAH experience dyspnea and exercise limitation — and as right ventricular (RV) failure develops, edema, exertional chest pain, syncope, and increased risk of death. PAH is most commonly idiopathic (IPAH) or associated with an underlying connective tissue disease (CTD-PAH), such as scleroderma1. In both IPAH and CTD-PAH patients, median survival is less than 3 years in the absence of therapy3,4,5. Research advances in our understanding of the pathobiology of PAH have led to the study, approval, and availability of many novel PAH-specific medications. These include prostanoid analogs (i.e., intravenous epoprostenol, subcutaneous/intravenous treprostinil), endothelin receptor antagonists (i.e., ambrisentan, bosentan), and phosphodiesterase type-5 inhibitors (i.e., sildenafil, tadalafil)2,6. What are the expectations of this array of therapies on the part of patients with PAH and their physicians? The published evidence, typically short-term, 3 to 4-month, randomized controlled trials of all these therapies, demonstrates benefit in both IPAH and CTD-PAH7. A majority of patients have small reductions in PAP and PVR, increased cardiac output, decreased symptoms, and increased exercise capacity, as measured by 6-minute walk test (6-MWT). New York Heart Association/World Health Organization (NYHA/WHO) functional class will improve in about one-third of patients, and objectively measured quality of life (QOL) may also improve2,6,7. A metaanalysis of published randomized controlled trials of PAH-specific therapies also confirmed a small, short-term survival benefit7. Thus, based on the evidence, patients with PAH and their physicians expect symptomatic benefit and improved functional capacity, important components … Address correspondence to Dr. S. Mehta, Division of Respirology, London Health Sciences Center, Victoria Hospital, Room E1.325, 800 Commissioner’s Road East, London, ON N6A 5W9, Canada. E-mail: sanjay.mehta{at}lhsc.on.ca

Does Grading the Severity of Gastroparesis Based on Scintigraphic Gastric Emptying Predict the Treatment Outcome of Patients with Gastroparesis?

The objectives of this study were as follows: (1) Whether gastric emptying is different between gastroparesis (GP) patients responding or not responding to standard medical therapy; (2) Identifying if mild, moderate, and severe degrees of gastroparesis based on the scintigraphic gastric emptying test (GET) can predict treatment responses for GP of diabetic (DM) and idiopathic (ID) origin. A total of 165 patients (119 F) diagnosed with GP [126 (76%) DM, 39 (24%) ID etiology] failed medical treatment and required the gastric electrical stimulation (GES) device (GES group). In addition, 112 patients (89 F) [37 (33%) DM, 75 (67%) ID] with GP who symptomatically responded to medical therapies are the comparison group (MED GP). All patients underwent a standardized scintigraphic GET consisting of low-fat (2%) isotope labeled egg beaters meal of 250 kcal. We also analyzed the GET data to find cut-off points for different degrees of GP and identified mild (11-20% retention), moderate (21-35%), and severe gastroparesis (>35%) based on percent retention of isotope at 4 h. Overall gastric retention at 4 h was significantly greater in the GES group (45±1.9%) than MED GP (30±2%) (p<0.001). The distribution severity of the GET was different in GES-treated patients than MED treated (p<0.001). In the diabetics, 57% of GES patients retained >35% after 4 h (severe) similar to 43% in the DM MED group. However, 50% of the ID GES patients had retention>35% at 4 h significantly more than only 17% of ID MED GP. Significantly more ID patients who responded to medical therapy had mild gastroparesis and significantly more requiring GES had severe GET (p<0.05). (1) GET in patients whose GP symptoms were refractory to standard medical therapy and required GES was significantly slower than in GP patients whose symptoms responded to medical therapy. (2) Stratifying GET into mild, moderate, and severe degrees of gastric retention does not predict whether a medical or surgical approach will be better to control the symptoms of diabetic GP but does correlate with treatment for the idiopathic GP subgroup.

PIES (Predictors of Improvement after Electrical Stimulation) in Gastroparesis

Purpose: Objective criteria to predict response to Gastric Electrical Stimulation (GES) in medically-refractory gastroparesis (GP) have not been identified. Temporary GES (tGES) (GIE. 2005;61:455–6) improves GP symptoms and may be used to assess response to permanent GES (pGES). We examined long term outcomes in a large group of GP patients to define clinical and tGES-derived mucosal electrogastrogram criteria that may predict outcome to pGES. Methods: 394 consecutive GP patients (320 F, 74 M, mean age 43 years) were consented for GES over 15 years, with diagnoses: 240 idiopathic (ID), 103 diabetes mellitus (D) and 51 post-surgical (PS). To predict response to pGES 150 patients underwent tGES prior to pGES (ID 88, D 40, PS 22). All patients were assessed by symptom scores [nausea (N), vomiting (V), and total symptom (TSS)] and IDIOMS (a HRQOL measure) at baseline (b), after tGES (t) and at the latest (L) follow-up after GES, as well as a ratio (Rt) of frequency to amplitude in tGES mucosal EGG. Linear regression determined independent variables predicting the latest vomiting score. Results: Median follow-up was 57 months (range 10 months to 12 years). In analysis by etiology, virtually all patients (I, P < 0.001, DM, P≤ 0.001 and PS, P≤ 0.001) had very good responses. Among all GP patients linear regression analysis identified 3 predictors of improvement in vomiting scores: pt age, baseline vomiting score and Rt. In subset analysis, these predictors were most significant for ID. Among all categories of GP, linear regression analysis identified a low Rt derived by the use of mEGG as the single best predictor of response to tGES and pGES. Conclusion: Permanent GES for severe GP results in significant and sustained improvement of overall symptoms and quality of life. The independent predictors of response (age, Vb score, and Rt) were most significant in ID patients. Rt derived from endoscopic tGES mucosal EGG is an accurate predictive criterion of symptom improvement with GES, especially improvement in vomiting. Future studies with larger sample sizes may identify and standardize these and other factors that may predict outcomes after GES.Table: Subset AnalysisFigureSymptom Outcome: IDIOMs, Nausea (N), vomiting (V) and total symptom score (TSS) at baseline (b) after temporary GES (tGES) and at the latest (last) date of evaluation (last). All parameters showed significant improvement (see text for P values)

Heart rate responses during the 6-minute walk test in pulmonary arterial hypertension

Patients with pulmonary arterial hypertension (PAH) exhibit a limited increase in stroke volume on exercise, and the heart rate (HR) increases may reflect the main mechanism that allows cardiac output to increase. The current prospective study documented the contribution of HR to the 6-min walking distance (6MWD) in idiopathic (IPAH) and nonidiopathic PAH. Eighty-three patients (46 IPAH and 37 nonidiopathic PAH) underwent haemodynamic evaluation and a 6MWD test. Chronotropic response (peak walking HR minus resting HR) and peripheral oxygen saturation were monitored. Fifty-seven patients were also assessed after 5+/-2 months of treatment (bosentan n = 38, epoprostenol n = 14, bosentan-epoprostenol n = 3, iloprost n = 2). Before treatment, the 6MWD was related to numerous demographic, haemodynamic and walking test characteristics. Stepwise regression analysis indicated that the only factors significantly associated with the 6MWD were stroke volume and chronotropic response in both IPAH and nonidiopathic PAH patients. Following treatment, changes in 6MWD were significantly related to changes in chronotropic response in both IPAH and nonidiopathic PAH. In conclusion, baseline stroke volume and chronotropic response were independently associated with the 6-min walking distance in pulmonary arterial hypertension. The lack of chronotropic response may reflect the loss in normal physiological reserve in more unwell patients.

Long-Term Outcome of Bosentan Treatment in Idiopathic Pulmonary Arterial Hypertension and Pulmonary Arterial Hypertension Associated with the Scleroderma Spectrum of Diseases

Bosentan improves clinical outcomes in pulmonary arterial hypertension (PAH), particularly in the idiopathic (IPAH) subset. Scant data are available regarding PAH associated with the scleroderma spectrum of diseases (APAH-SSD). Here we review our experience with bosentan in these 2 groups. Included were all patients at our center with either IPAH or APAH-SSD in whom bosentan was the first-line, single-agent therapy with at least 6 months of follow-up. Changes in the World Health Organization (WHO) functional class from baseline to the most recent follow-up on monotherapy were compared between the 2 groups, as well as overall survival and time to a composite end point of hepatotoxicity requiring discontinuation, use of additional therapy, or death. Nineteen IPAH and 17 APAH-SSD subjects with similar baseline clinical characteristics and a median follow-up 9 months (range, 6-44) were analyzed. In IPAH subjects, WHO class improved from 3.1 +/- 0.5 at baseline to 2.4 +/- 0.8 (p = 0.005). No change occurred in the APAH-SSD group: 2.9 +/- 0.3 vs. 2.8 +/- 0.8; p = 0.5. Hepatotoxicity requiring discontinuation developed in 6 patients (17%). Seven (37%) IPAH and 8 SSD patients (47%) reached the composite end point (p = NS). Overall survival at 1 and 2 years was 100% and 100% vs 87% and 79% for IPAH and APAH-SSD patients, respectively (p = 0.075). First-line bosentan monotherapy is associated with long-term improvement in functional class and good overall survival in patients with WHO class III IPAH. Most APAH-SSD patients experienced stability or decline in functional class and tended to have a higher mortality.

Coenzyme Q10 levels in idiopathic and varicocele-associated asthenozoospermia.

Levels of coenzyme Q10 (CoQ10) and of its reduced and oxidized forms (ubiquinol, QH2, and ubiquinone, Qox) have been determined in sperm cells and seminal plasma of idiopathic (IDA) and varicocele-associated (VARA) asthenozoospermic patients and of controls. The results have shown significantly lower levels of coenzyme Q10 and of its reduced form, QH2, in semen samples from patients with asthenospermia; furthermore, the coenzyme Q10 content was mainly associated with spermatozoa. Interestingly, sperm cells from IDA patients exhibited significantly lower levels of CoQ10 and QH2 when compared to VARA ones. The QH2/Qox ratio was significantly lower in sperm cells from IDA patients and in seminal plasma from IDA and VARA patients when compared with the control group. The present data suggest that the QH2/Qox ratio may be an index of oxidative stress and its reduction, a risk factor for semen quality. Therefore, the present data could suggest that sperm cells, characterized by low motility and abnormal morphology, have low levels of coenzyme Q10. As a consequence, they could be less capable in dealing with oxidative stress which could lead to a reduced QH2/Qox ratio. Furthermore, the significantly lower levels of CoQ10 and QH2 levels in sperm cells from IDA patients, when compared to VARA ones, enable us to hypothesize a pathogenetic role of antioxidant impairment, at least as a cofactor, in idiopathic forms of asthenozoospermia.