Enhancing treatment effects by combining continuous theta burst stimulation with smooth pursuit training

Continuous theta burst stimulation (cTBS) represents a promising approach in the treatment of neglect syndrom. However, it is not known whether cTBS in conjunction with another technique may enhance the therapeutic effects. In the present sham-controlled study, we aimed to combine cTBS with smooth pursuit training (SPT), another method known to effectively improve neglect symptoms, and to evaluate whether this combination would result in a stronger effect than SPT alone. Eighteen patients with left spatial neglect after right-hemispheric stroke were included in the study and performed a cancellation task on a large 54.6" touchscreen monitor. A sequential application of cTBS and SPT induced a significantly greater improvement of neglect than SPT alone. After the combined application of these two methods, patients detected significantly more targets and their cancellation behaviour presented a significantly greater shift towards the contralesional hemispace. We suggest that a combined, sequential application of cTBS and SPT is a promising new approach to treat neglect.

Acupuncture-induced changes of pressure pain threshold are mediated by segmental inhibition-a randomized controlled trial

Our aim was to distinguish between spinal and supraspinal mechanisms in the intact nervous system by comparing homosegmental and heterosegmental effects of electroacupuncture (EA) and manual acupuncture (MA) on sensory perception in healthy volunteers by means of quantitative sensory testing. Seventy-two healthy volunteers were randomly assigned to receive either MA or EA at SP 6, SP 9, GB 39, and ST 36 at the left leg or relaxed for 30 minutes (control group [CG]). Blinded examiners assessed 13 sensory modalities (thermal and mechanical detection and pain thresholds) at the upper arms and lower legs before and after intervention by means of a standardized quantitative sensory testing battery. Change scores of all 13 sensory thresholds were compared between groups. The main outcome measure was the change score of the pressure pain threshold (PPT). There were no baseline differences between groups. Pressure pain threshold change scores at the lower left leg, in the same segment as the needling site, differed significantly (P = 0.008) between the EA (median: 103.01 kPa) and CG groups (median: 0.00 kPa) but not between the MA (median: 0.00 kPa) and CG groups. No further significant change score differences were found between one of the acupuncture groups and the CG. The PPT can be changed by EA. The PPT increase was confined to the segment of needling, which indicates that it is mainly mediated by segmental inhibition in the spinal cord. This underscores the importance of segmental needling and electrical stimulation in clinical practice.

Tibial Nerve Stimulation for Treating Neurogenic Lower Urinary Tract Dysfunction: A Systematic Review

CONTEXT Tibial nerve stimulation (TNS) is a promising therapy for non-neurogenic lower urinary tract dysfunction and might also be a valuable option for patients with an underlying neurological disorder. OBJECTIVE We systematically reviewed all available evidence on the efficacy and safety of TNS for treating neurogenic lower urinary tract dysfunction (NLUTD). EVIDENCE ACQUISITION The review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement. EVIDENCE SYNTHESIS After screening 1943 articles, 16 studies (4 randomized controlled trials [RCTs], 9 prospective cohort studies, 2 retrospective case series, and 1 case report) enrolling 469 patients (283 women and 186 men) were included. Five studies reported on acute TNS and 11 on chronic TNS. In acute and chronic TNS, the mean increase of maximum cystometric capacity ranged from 56 to 132mL and from 49 to 150mL, and the mean increase of bladder volume at first detrusor overactivity ranged from 44 to 92mL and from 93 to 121mL, respectively. In acute and chronic TNS, the mean decrease of maximum detrusor pressure during the storage phase ranged from 5 to 15cm H2O and from 4 to 21cm H2O, respectively. In chronic TNS, the mean decrease in number of voids per 24h, in number of leakages per 24h, and in postvoid residual ranged from 3 to 7, from 1 to 4, and from 15 to 55mL, respectively. No TNS-related adverse events have been reported. Risk of bias and confounding was high in most studies. CONCLUSIONS Although preliminary data of RCTs and non-RCTs suggest TNS might be effective and safe for treating NLUTD, the evidence base is poor, derived from small, mostly noncomparative studies with a high risk of bias and confounding. More reliable data from well-designed RCTs are needed to reach definitive conclusions. PATIENT SUMMARY Early data suggest tibial nerve stimulation might be effective and safe for treating neurogenic lower urinary tract dysfunction, but more reliable evidence is required.

Transcutaneous Electrical Nerve Stimulation for Treating Neurogenic Lower Urinary Tract Dysfunction: A Systematic Review

CONTEXT Transcutaneous electrical nerve stimulation (TENS) is a promising therapy for non-neurogenic lower urinary tract dysfunction and might also be a valuable option in patients with an underlying neurological disorder. OBJECTIVE We systematically reviewed all available evidence on the efficacy and safety of TENS for treating neurogenic lower urinary tract dysfunction. EVIDENCE ACQUISITION The review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement. EVIDENCE SYNTHESIS After screening 1943 articles, 22 studies (two randomised controlled trials, 14 prospective cohort studies, five retrospective case series, and one case report) enrolling 450 patients were included. Eleven studies reported on acute TENS and 11 on chronic TENS. In acute TENS and chronic TENS, the mean increase of maximum cystometric capacity ranged from 69ml to 163ml and from 4ml to 156ml, the mean change of bladder volume at first detrusor overactivity from a decrease of 13ml to an increase of 175ml and from an increase of 10ml to 120ml, a mean decrease of maximum detrusor pressure at first detrusor overactivity from 18 cmH20 to 72 cmH20 and 8 cmH20, and a mean decrease of maximum storage detrusor pressure from 20 cmH20 to 58 cmH2O and from 3 cmH20 to 8 cmH2O, respectively. In chronic TENS, a mean decrease in the number of voids and leakages per 24h ranged from 1 to 3 and from 0 to 4, a mean increase of maximum flow rate from 2ml/s to 7ml/s, and a mean change of postvoid residual from an increase of 26ml to a decrease of 85ml. No TENS-related serious adverse events have been reported. Risk of bias and confounding was high in most studies. CONCLUSIONS Although preliminary data suggest TENS might be effective and safe for treating neurogenic lower urinary tract dysfunction, the evidence base is poor and more reliable data from well-designed randomised controlled trials are needed to make definitive conclusions. PATIENT SUMMARY Early data suggest that transcutaneous electrical nerve stimulation might be effective and safe for treating neurogenic lower urinary tract dysfunction, but more reliable evidence is required.

The role of interleukin-6 in the angiogenesis of ovarian carcinoma

The purpose of this study was to characterize the effects of IL-6 on endothelial cells and to investigate the role of IL-6 in the angiogenesis of ovarian carcinomas. We evaluated human ovarian carcinoma clinical specimens and determined that high expression of IL-6 was associated with increased tumor vascularization. Additionally, endothelial cells derived from the ovary and mesentery expressed the IL-6 receptor (IL-6R), and their stimulation with the exogenous ligand activated downstream signaling molecules and enhanced cell migration. Dual immunohistochemical staining for CD-31 and IL-6R revealed IL-6R expression on human endothelial cells within normal ovary and ovarian carcinomas. To further investigate the possible proangiogenic function of IL-6, Gelfoam sponges containing IL-6 or bFGF were implanted into the subcutis of BALB/c mice. IL-6 containing sponges were vascularized to the same extent as bFGF containing sponges. ^ Chronic stress can adversely affect disease progression. Stimulation of ovarian carcinoma cell lines with concentrations of catecholamines achieved in individuals experiencing chronic stress resulted in a substantial increase in IL-6 production. It was determined that stress mediators regulate IL-6 expression through the β-adrenergic receptor and Src. These data illustrate one mechanism by which chronic stress may influence tumor progression. ^ To investigate whether IL-6 contributes to the angiogenesis of ovarian carcinomas, we isolated low IL-6 expressing clones from the SKOV3.ip1 cell line and transfected them with a plasmid encoding the IL-6 gene. We observed no difference in tumor weight between high and low IL-6 expressing cells. However, while low IL-6 expressing tumors were highly vascularized, high IL-6 expressing tumors appeared hypervascularized. Immunohistochemical analysis revealed that all tumors exhibited robust expression of additional proangiogenic molecules. ^ Collectively, these studies indicate that IL-6 secreted by ovarian cancer cells is a highly proangiogenic cytokine. However, IL-6 is but one of several proangiogenic molecules produced by ovarian cancer, and its inhibition may not be sufficient to inhibit angiogenesis of ovarian carcinoma. The findings presented in this dissertation provide insight into the function of IL-6 as a regulator of angiogenesis. Understanding of the role of proangiogenic molecules such as IL-6 in ovarian carcinoma may have important implications for therapy directed at the vascular component of this disease. ^

Defective antitumor function of monocyte -derived macrophages from epithelial ovarian cancer patients

An abundance of monocytes and macrophages (MO/MA) in the microenvironment of epithelial ovarian cancer (EOC) suggests possible dual roles for these cells. Certain MO/MA subpopulations may inhibit tumor growth by antibody-dependent cell-mediated cytotoxicity (ADCC), phagocytosis, or stimulation of adaptive immunity. In contrast, other MO/MA subpopulations may support tumor growth by immunosuppressive or pro-angiogenic cytokine production. A better understanding of the phenotype and activity of MO/MA in EOC should lead to greater insight into their role in the immunopathobiology of EOC and hence suggest targets for treatment. We have found differences in the proportions of MO/MA subpopulations in the peripheral blood and ascites of EOC patients compared to normal donors, and differences in MO/MA surface phenotype in the associated tumor environment compared to the systemic circulation. We also demonstrate that, following their activation in vitro, monocyte-derived macrophages (MDM) from the peripheral blood and ascites of EOC patients exhibit antitumor effector activities that are different from the behavior of normal donor cells. The phenotypic characteristics and antitumor activity of CD14+ MO/MA and an isolated subpopulation of CD14brightCD16 −HLA-DR+ MO/MA were compared in samples of normal donor peripheral blood and the peripheral blood and ascites from EOC patients. MDM were cultured with macrophage colony-stimulating factor (M-CSF) and activated with lipopolysaccharide (LPS) or a combination of LPS plus recombinant interferon-gamma. We determined that MO/MA from EOC patients had altered morphology and significantly less ADCC and phagocytic activity than did MO/MA from normal donors. ADCC and phagocytosis are mediated by receptors for the Fe portion of IgG (FcγRs), the expression of which were also found to be deficient on EOC MDM from peripheral blood and ascites. Anti-tumor functions not mediated by the FcγRs, such as macrophage mediated cytotoxicity and cytostasis, were not impaired in EOC MDM compared to normal donor MDM. Our findings also showed that MDM from both EOC patients and normal donors produce M-CSF-stimulated cytokines, including interleukin-8, tumor necrosis factor alpha, and interleukin-6, which have the potential to support ovarian tumor growth and metastasis. These findings may be relevant to the pathogenesis of EOC and to the development of future bioimmunotherapeutic strategies. ^

Increased B-lymphopoiesis by interleukin 7 induces bone loss in mice with intact ovarian function: Similarity to estrogen deficiency

Estrogen deficiency caused by ovariectomy (OVX) results in a marked bone loss due to stimulated bone resorption by osteoclasts. During our investigations of the pathogenesis of bone loss in estrogen deficiency, we found that OVX selectively stimulates B-lymphopoiesis which results in marked accumulation of B220-positive pre-B cells in mouse bone marrow. To examine the possible correlation between stimulated B-lymphopoiesis and bone loss, 8-week-old female mice were treated with interleukin (IL) 7, which stimulates B-lymphopoiesis in bone marrow. We also examined bone mass in IL-7 receptor-knockout mice that exhibit marked suppression of B-lymphopoiesis in the bone marrow. The increased B-lymphopoiesis induced by IL-7 administration resulted in marked bone loss by stimulation of osteoclastic bone resorption in mice with intact ovarian function. The changes in both B-lymphopoiesis and bone mass in IL-7-treated female mice were similar to those in age-matched OVX mice. In contrast, the trabecular bone volume of the femur was greatly increased in both female and male IL-7 receptor-knockout mice when compared with the respective wild-type and heterozygous littermates. These results show that the perturbation of B-lymphopoiesis in the bone marrow is closely linked to the change in bone mass. We propose here that the increased B-lymphopoiesis due to estrogen deficiency is involved in the mechanism of stimulated bone resorption.

Loss of ovarian function promotes angiogenesis in human ovarian carcinoma

We show here that elevated levels of gonadotropins (luteinizing hormone and follicle stimulating hormone), as found in menopause or after ovariectomy, promote growth of human ovarian carcinoma by induction of tumor angiogenesis. Human epithelial ovarian cancer tumors progressed faster in ovariectomized mice. This induced growth could be attributed to the elevated levels of gonadotropins associated with loss of ovarian function because direct administration of gonadotropins also was effective in promoting tumor progression in vivo. On the other hand, gonadotropins had no direct effect on the proliferation of human ovarian cancer cells in vitro. Using MRI, we demonstrated that ovariectomy significantly (P < 0.02) induces neovascularization of human ovarian carcinoma spheroids implanted in nude mice. Moreover, conditioned medium of gonadotropin-treated human ovarian carcinoma cells showed increased mitogenic activity to bovine endothelial cells, and this activity could be blocked by neutralizing antibodies against luteinizing hormone and against vascular endothelial growth factor. Accordingly, gonadotropin stimulation resulted in a dose-dependent-induced expression of vascular endothelial growth factor in monolayer culture as well as in the outer proliferating cells of human ovarian cancer spheroids. These results demonstrate the significance of the elevated levels of gonadotropins, as found in menopause and in all ovarian cancer patients, on the progression of ovarian cancer and could explain the protective effect of estrogen replacement therapy. Based on these results, we suggest that hormonal therapy aimed at lowering the circulating levels of gonadotropins may possibly prolong remission in ovarian cancer by extending tumor dormancy.

Insulin-induced Stimulation of Na+,K+-ATPase Activity in Kidney Proximal Tubule Cells Depends on Phosphorylation of the α-Subunit at Tyr-10

Phosphorylation of the α-subunit of Na+,K+-ATPase plays an important role in the regulation of this pump. Recent studies suggest that insulin, known to increase solute and fluid reabsorption in mammalian proximal convoluted tubule (PCT), is stimulating Na+,K+-ATPase activity through the tyrosine phosphorylation process. This study was therefore undertaken to evaluate the role of tyrosine phosphorylation of the Na+,K+-ATPase α-subunit in the action of insulin. In rat PCT, insulin and orthovanadate (a tyrosine phosphatase inhibitor) increased tyrosine phosphorylation level of the α-subunit more than twofold. Their effects were not additive, suggesting a common mechanism of action. Insulin-induced tyrosine phosphorylation was prevented by genistein, a tyrosine kinase inhibitor. The site of tyrosine phosphorylation was identified on Tyr-10 by controlled trypsinolysis in rat PCTs and by site-directed mutagenesis in opossum kidney cells transfected with rat α-subunit. The functional relevance of Tyr-10 phosphorylation was assessed by 1) the abolition of insulin-induced stimulation of the ouabain-sensitive 86Rb uptake in opossum kidney cells expressing mutant rat α1-subunits wherein tyrosine was replaced by alanine or glutamine; and 2) the similarity of the time course and dose dependency of the insulin-induced increase in ouabain-sensitive 86Rb uptake and tyrosine phosphorylation. These findings indicate that phosphorylation of the Na+,K+-ATPase α-subunit at Tyr-10 likely participates in the physiological control of sodium reabsorption in PCT.

Stimulation of ionotropic glutamate receptors activates transcription factor NF-kappa B in primary neurons.

L-Glutamate is the most common excitatory neurotransmitter in the brain and plays a crucial role in neuronal plasticity as well as in neurotoxicity. While a large body of literature describes the induction of immediate-early genes, including c-fos, fosB, c-jun, junB, zif/268, and krox genes by glutamate and agonists in neurons, very little is known about preexisting transcription factors controlling the induction of such genes. This prompted us to investigate whether stimulation of glutamate receptors can activate NF-kappa B, which is present in neurons in either inducible or constitutive form. Here we report that brief treatments with kainate or high potassium strongly activated NF-kappa B in granule cells from rat cerebellum. This was detected at the single cell level by immunostaining with a monoclonal antibody that selectively reacts with the transcriptionally active, nuclear form of NF-kappa B p65. The activation of NF-kappa B could be blocked with the antioxidant pyrrolidine dithiocarbamate, suggesting the involvement of reactive oxygen intermediates. The data may explain the kainate-induced cell surface expression of major histocompatibility complex class I molecules, which are encoded by genes known to be controlled by NF-kappa B. Moreover, NF-kappa B activity was found to change dramatically in neurons during development of the cerebellum between days 5 and 7 after birth.

Aod1, the immunoregulatory locus controlling abrogation of tolerance in neonatal thymectomy-induced autoimmune ovarian dysgenesis, maps to mouse chromosome 16.

Mice thymectomized at three days of age (D3Tx) develop during adulthood a variety of organ-specific autoimmune diseases, including autoimmune ovarian dysgenesis (AOD). The phenotypic spectrum of AOD is characterized by the development of anti-ovarian autoantibodies, oophoritis, and atrophy. The D3Tx model of AOD is unique in that disease induction depends exclusively on perturbation of the normal developing immune system, is T-cell-mediated, and is strain specific. For example, D3Tx A/J mice are highly susceptible to AOD, whereas C57BL/6J mice are resistant. After D3Tx, self ovarian antigens, expressed at physiological levels, trigger an autoimmune response capable of eliciting disease. The D3Tx model provides, therefore, the opportunity to focus on the mechanisms of self-tolerance that are relevant to disease pathogenesis. Previous studies indicate that the principal mechanisms involved in AOD susceptibility are genetically controlled and govern developmental processes associated with the induction and maintenance of peripheral tolerance. We report here the mapping of the Aod1 locus to mouse chromosome 16 within a region encoding several loci of immunologic relevance, including scid, Igl1, VpreB, Igll, Igl1r, Mtv6 (Mls-3), Ly-7, Ifnar, and Ifgt.

A randomized controlled trial of intensive neurophysiology education in chronic low back pain

Objectives: Cognitive-behavioral pain management programs typically achieve improvements in pain cognitions, disability, and physical performance. However, it is not known whether the neurophysiology education component of such programs contributes to these outcomes. In chronic low back pain patients, we investigated the effect of neurophysiology education on cognitions, disability, and physical performance. Methods: This study was a blinded randomized controlled trial. Individual education sessions on neurophysiology of pain (experimental group) and back anatomy and physiology (control group) were conducted by trained physical therapist educators. Cognitions were evaluated using the Survey of Pain Attitudes (revised) (SOPA(R)), and the Pain Catastrophizing Scale (PCS). Behavioral measures included the Roland Morris Disability Questionnaire (RMDQ), and 3 physical performance tasks; (1) straight leg raise (SLR), (2) forward bending range, and (3) an abdominal drawing-in task, which provides a measure of voluntary activation of the deep abdominal muscles. Methodological checks evaluated non-specific effects of intervention. Results: There was a significant treatment effect on the SOPA(R), PCS, SLR, and forward bending. There was a statistically significant effect on RMDQ; however, the size of this effect was small and probably not clinically meaningful. Discussion: Education about pain neurophysiology changes pain cognitions and physical performance but is insufficient by itself to obtain a change in perceived disability. The results suggest that pain neurophysiology education, but not back school type education, should be included in a wider pain management approach.

Brain activity modifications following spinal cord stimulation for chronic neuropathic pain:a systematic review

Background and objective: Spinal cord stimulation (SCS) is believed to exert supraspinal effects; however, these mechanisms are still far from fully elucidated. This systematic review aims to assess existing neurophysiological and functional neuroimaging literature to reveal current knowledge regarding the effects of SCS for chronic neuropathic pain on brain activity, to identify gaps in knowledge, and to suggest directions for future research. Databases and data treatment: Electronic databases and hand-search of reference lists were employed to identify publications investigating brain activity associated with SCS in patients with chronic neuropathic pain, using neurophysiological and functional neuroimaging techniques (fMRI, PET, MEG, EEG). Studies investigating patients with SCS for chronic neuropathic pain and studying brain activity related to SCS were included. Demographic data (age, gender), study factors (imaging modality, patient diagnoses, pain area, duration of SCS at recording, stimulus used) and brain areas activated were extracted from the included studies. Results: Twenty-four studies were included. Thirteen studies used neuroelectrical imaging techniques, eight studies used haemodynamic imaging techniques, two studies employed both neuroelectrical and haemodynamic techniques separately, and one study investigated cerebral neurobiology. Conclusions: The limited available evidence regarding supraspinal mechanisms of SCS does not allow us to develop any conclusive theories. However, the studies included appear to show an inhibitory effect of SCS on somatosensory evoked potentials, as well as identifying the thalamus and anterior cingulate cortex as potential mediators of the pain experience. The lack of substantial evidence in this area highlights the need for large-scale controlled studies of this kind.

Efetividade das correntes TENS (Transcutaneous Electrical Nerve Stimulation) na promoção do processo de cicatrização de feridas crónicas: revisão sistemática

Introdução: As feridas crónicas têm um impacto bastante significativo em várias componentes, tais como a física, psicológica e financeira. Estudos efetuados no âmbito da estimulação elétrica (EE) na cicatrização de feridas crónicas mostraram que as correntes bidirecionais, como o TENS (transcutaneous electrical nerve stimulation), parecem ser promissoras. Objetivo: Descrever analiticamente os efeitos das correntes TENS na promoção da cicatrização de feridas crónicas. Métodos: O estudo que efetuámos trata-se de uma revisão sistemática. As bases de dados utilizadas foram: MEDLINE/PubMed, Cochrane Central Register of Controlled Trials, B-on, PEDro. Foram incluídos estudos realizados em humanos com idades superiores ou iguais a 18 anos, podendo ser randomizados ou não. Estes estudos deviam de ter como outcome a taxa de cicatrização. A qualidade dos artigos foi avaliada pela escala PEDro. Resultados: Dos 2505 artigos encontrados, incluímos 14 estudos (7 randomizados e 7 não-randomizados). Destes estudos, 5 focam-se nas feridas diabéticas, 3 incidem nas úlceras de pressão, 1 inclui úlceras venosas e 5 englobam mais do que um tipo de feridas crónicas. A média de idades em todos os estudos varia de 31,1 e 73,1 anos, sendo que o número da amostra varia de 20 a 214 indivíduos. Todos os artigos apresentaram resultados positivos na taxa de cicatrização aquando da aplicação das correntes TENS em qualquer tipo de feridas crónicas. O estudo apresenta algumas limitações na qualidade metodológica e no processo de seleção dos ensaios. Conclusão: A terapia TENS parece ser uma modalidade terapêutica efetiva na promoção do processo de cicatrização de feridas crónicas.

Ovarian suppression using luteinizing hormonereleasing hormone agonists during chemotherapy to preserve ovarian function and fertility of breast cancer patients: A meta-analysis of randomized studies

Background: The role of temporary ovarian suppression with luteinizing hormone-releasing hormone agonists (LHRHa) in the prevention of chemotherapy-induced premature ovarian failure (POF) is still controversial. Our meta-analysis of randomized, controlled trials (RCTs) investigates whether the use of LHRHa during chemotherapy in premenopausal breast cancer patients reduces treatment-related POF rate, increases pregnancy rate, and impacts disease-free survival (DFS). Methods: A literature search using PubMed, Embase, and the Cochrane Library, and the proceedings of major conferences, was conducted up to 30 April 2015. Odds ratios (ORs) and 95% confidence intervals (CIs) for POF (i.e. POF by study definition, and POF defined as amenorrhea 1 year after chemotherapy completion) and for patients with pregnancy, as well hazard ratios (HRs) and 95% CI for DFS, were calculated for each trial. Pooled analysis was carried out using the fixed- and random-effects models. Results: A total of 12 RCTs were eligible including 1231 breast cancer patients. The use of LHRHa was associated with a significant reduced risk of POF (OR 0.36, 95% CI 0.23-0.57; P < 0.001), yet with significant heterogeneity (I2 = 47.1%, Pheterogeneity = 0.026). In eight studies reporting amenorrhea rates 1 year after chemotherapy completion, the addition of LHRHa reduced the risk of POF (OR 0.55, 95% CI 0.41-0.73, P < 0.001) without heterogeneity (I2 = 0.0%, Pheterogeneity = 0.936). In five studies reporting pregnancies, more patients treated with LHRHa achieved pregnancy (33 versus 19 women; OR 1.83, 95% CI 1.02-3.28, P = 0.041; I2 = 0.0%, Pheterogeneity = 0.629). In three studies reporting DFS, no difference was observed (HR 1.00, 95% CI 0.49-2.04, P = 0.939; I2 = 68.0%, Pheterogeneity = 0.044). Conclusion: Temporary ovarian suppression with LHRHa in young breast cancer patients is associated with a reduced risk of chemotherapy-induced POF and seems to increase the pregnancy rate, without an apparent negative consequence on prognosis.