| 1. |
- Lundin, Anna-Carin
(författare)
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Tendinosis in Trigger Finger
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Trigger finger is one of the most common hand conditions, with a prevalence of almost 3%. The aetiology remains unclear even though many causes have been suggested. The prevailing paradigm is that the pathogenesis of trigger finger is ascribed to primary changes in the first fibrous condensation of the tendon sheath (A1-pulley). Several studies have investigated pathology in the pulley, but few have investigated the tendon. The general aim of this thesis was to find out if there is pathology in the trigger finger tendon and to define it.We first looked at trigger finger tendon biopsies in a light microscope, and found that they were histologically different from healthy tendons. They showed signs of micro-ruptures, collagen degradation, increased amounts of ground substance, both hyper- and hypo-cellular areas, round active cell nuclei and absence of inflammatory cells, all similar to tendinosis. The histological picture was further assessed by using a scoring system for Achilles tendinosis. The trigger finger tendons scored high, suggesting a similar histopathology.Next, we performed a quantitative real-time polymerase chain reaction (qPCR) on trigger finger tendons. We assessed the mRNA expression of 10 genes, which have been described to be differently expressed in Achilles tendinosis (collagen 1 and 3, versican, decorin, biglycan, aggrecan, MMP-2, MMP-3, ADAMTS-5, and TIMP-3). The overall expression pattern agreed with previous studies on Achilles tendinosis, suggesting that the cellular function in trigger finger tendons is disturbed in a similar way as in Achilles tendinosis.Recent experimental and observational research has suggested potential side effects of statin treatment on tendons, but firm evidence was lacking. We performed an epidemiological study on two large population-based cohorts. Statin use was found to increase the risk of both trigger finger and tendinosis in the shoulder and Achilles tendons, especially among men. This suggests a similar pathology in trigger finger and tendinosis.We have also studied the time to treatment effect after a single injection of glucocorticoid in trigger finger. Our results suggest that 60-80% of patients can expect resolution of the triggering within 14 days, and half of them within seven days. This result allows correct information to be given to the patient and proper planning of follow-ups.In conclusion, the pathology in trigger finger tendons is similar to tendinosis in other tendons.
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| 2. |
- Nord, Maria
(författare)
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Levodopa pharmacokinetics -from stomach to brain : A study on patients with Parkinson’s disease
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Parkinson’s disease (PD) is one of the most common neurodegenerative disorders and it is caused by a loss of dopamine (DA) producing neurons in the basal ganglia in the brain. The PD patient suffers from motor symptoms such as tremor, bradykinesia and rigidity and treatment with levodopa (LD), the precursor of DA, has positive effects on these symptoms. Several factors affect the availability of orally given LD. Gastric emptying (GE) is one factor and it has been shown to be delayed in PD patients resulting in impaired levodopa uptake. Different enzymes metabolize LD on its way from the gut to the brain resulting in less LD available in the brain and more side effects from the metabolites. By adding dopa decarboxylase inhibitors (carbidopa or benserazide) or COMT-inhibitors (e.g. entacapone) the bioavailability of LD increases significantly and more LD can pass the blood-brain-barrier and be converted to DA in the brain. It has been considered of importance to avoid high levodopa peaks in the brain because this seems to induce changes in postsynaptic dopaminergic neurons causing disabling motor complications in PD patients. More continuously given LD, e.g. duodenal or intravenous (IV) infusions, has been shown to improve these motor complications. Deep brain stimulation of the subthalamic nucleus (STN DBS) has also been proven to improve motor complications and to make it possible to reduce the LD dosage in PD patients.In this doctoral thesis the main purpose is to study the pharmacokinetics of LD in patients with PD and motor complications; in blood and subcutaneous tissue and study the effect of GE and PD stage on LD uptake and the effect of continuously given LD (CDS) on LD uptake and GE; in blood and cerebrospinal fluid (CSF) when adding the peripheral enzyme inhibitors entacapone and carbidopa to LD infusion IV; in brain during STN DBSand during oral or IV LD treatment.To conclude, LD uptake is more favorable in PD patients with less severe disease and GE is delayed in PD patients. No obvious relation between LD uptake and GE or between GE and PD stage is seen and CDS decreases the LD levels. Entacapone increases the maximal concentration of LD in blood and CSF. This is more evident with additional carbidopa and important to consider in avoiding high LD peaks in brain during PD treatment. LD in brain increases during both oral and IV LD treatment and the DA levels follows LD well indicating that PD patients still have capacity to metabolize LD to DA despite probable pronounced nigral degeneration. STN DBS seems to increase putaminal DA levels and together with IV LD treatment also increases LD in brain possibly explaining why it is possible to decrease LD medication after STN DBS surgery.
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| 3. |
- Khoshnood, Ardavan
(författare)
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Prehospital Diagnosis and Oxygen Treatment in ST Elevation Myocardial Infarction
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- IntroductionPaper I: An Artificial Neural Network (ANN) was constructed to identify ST Elevation Myocardial Infarction (STEMI) and predict the need for Percutaneous Coronary Intervention (PCI). Paper II, III and IV: Studies suggest that O2 therapy may be harmful in STEMI patients. We therefore conducted the SOCCER study to evaluate the effects of O2 therapy in STEMI patients.MethodsPaper I: 560 ambulance ECGs sent to the Cardiac Care Unit (CCU), was together with the CCU physicians interpretation and decision of conducting an acute PCI or not collected, and compared with the interpretation and PCI decision of the ANN. Paper II, III, IV: Normoxic (≥94%) STEMI patients accepted for acute PCI were in the ambulance randomized to standard care with 10 L/min O2 or room air. A subset of the patients underwent echocardiography for determination of the Left Ventricular Ejection Fraction (LVEF) and the Wall Motion Score Index (WMSI). All patients had a Cardiac Magnetic Resonance Imaging (CMRI) to evaluate Myocardial area at Risk (MaR), Infarct Size (IS) and Myocardial Salvage Index (MSI).ResultsPaper I: The area under the ANN’s receiver operating characteristics curve for STEMI detection as well as predicting the need of acute PCI were very good.Paper II, III, IV: No significant differences could be shown in discussing MaR, MSI or IS between the O2 group (n=46) and the air group (n=49). Neither could any differences be shown for LVEF and WMSI at the index visit as well after six months between the O2 group (n=46) and the air group (n=41)ConclusionsPaper I: The results indicate that the number of ECGs sent to the CCU could be reduced with 2/3 as the ANN would safely identify ECGs not being STEMI.Paper II, III, IV: The results suggest that it is safe to withhold O2 therapy in normoxic, stable STEMI patients.
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| 4. |
- Pettersson, Ulrika, 1970-
(författare)
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Bone mass in the young athlete
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Bone mass and bone size accumulate during childhood and adolescence and peak in the twenties. The obtained peak bone mass has been suggested to be a major determinant of bone mass even in the very elderly. Although, genetic factors are the main determinants, environmental and lifestyle factors also play a crucial role in modulating maximal bone mass. Assessing these lifestyle factors would be of great importance for the intervention strategies against osteoporosis. The first aim of this thesis was to compare the bone mass and bone size in male and female young adults on a high level of physical activity with males or females on a low level of physical activity. Furthermore, it also aimed to investigate the influence of pubertal maturity, menstrual disturbances, and different body constitutional factors on bone mass and size during adolescence and young adulthood. The female activity groups consisted of cross-county skiers, soccer players, and rope skippers. Compared to their age-matched inactive controls, all these athletic groups demonstrated a significantly higher bone mineral density (BMD) at those sites subjected to the sport-specific loading. Rope-skipping, a very high impact activity was associated with a higher bone size, preferentially in the lower extremity, suggesting an effect of weight-bearing activity also on bone geometry. The effect of menstrual disturbances was evaluated in a group of long-distance runners, where amenorrheic runners had significantly lower BMD in both trabecular and also cortical bone in the lower extremity compared to eumenorrheic runners, suggesting that weight-bearing activity cannot compensate for the shortfall of reduced estrogen levels. The male activity groups consisted of ice hockey players and badminton players. Compared to their age-matched controls, both athletic groups demonstrated a significantly higher BMD at those sites subjected to the sport-specific loading. Especially badminton was associated with a high BMD, suggesting that physical activity, including jumps in unusual directions has a great osteogenic potential. The main determinants of BMD in both male and females were, except for type of physical activity, activity, muscle strength, height, and different body constitutional factors. However, the relationships with muscle strength and body constitution were somewhat weaker in the athletic groups, especially in the males, indicating that impact forces may be of greater importance in regulating bone mass in highly trained athletes. Yet bone size was largely determined by parameters related to body size and less strongly to physical activity. In a prospective study on adolescent boys, the changes in bone mass during late puberty were mainly accounted for by growth and development, including height and pubertal maturation, and less to physical activity level. Thus, the osteogenic effect from physical activity seems to be of importance for bone mass achievement predominantly before late puberty.
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| 5. |
- Gunnarsson, Salina
(författare)
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Synergistic effects of mesenchymal stromal cells and immunotherapy in experimental brain tumors
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain tumor. In spite of surgical resection, combined radiation therapy and chemotherapy, the mean survival is less than 15 months following diagnosis. Using the established N29 and N32 animal models of glioma, shown to have many similarities with the human tumor, we are able to study and develop therapeutic strategies against GBM. The tumor models were first characterized according to cancer-initiating capacity. It was established that both models concomitantly and homogenously express several immature and mature markers of neural origin. Furthermore, the glioma cells were highly clonogenic in vitro and showed a robust tumorigenicity in vivo. Next multipotent mesenchymal stromal cells (MSCs) were compared to neural precursor cells (NPCs) in capacity of survival and migration following intratumoral grafting, which revealed that MSCs were superior to NPCs as potential vectors in tumor therapy. It was also concluded that MSCs do not migrate towards a pre-established tumor when grafted behind it or in contact with the corpus callosum. Neither do the MSCs proliferate following grafting, further confirming that MSCs are suitable as cellular vehicles. MSCs derived from adult rat bone marrow are relatively easily isolated and cultured as well as able to be stably transduced to express a therapeutic gene/drug. When MSCs are grafted intratumorally following peripheral immunizations with IFNγ-secreting autologous irradiated tumor cells, a synergistic effect on anti-tumor immunity is noticed with a prolonged survival and an increased tumor infiltration of immune cells. Rat MSCs were modified to produce the cytokine interleukin 7 (IL-7), a growth factor for immune cells. IL-7 secreting MSCs injected intratumorally resulted in a decreased tumor area compared to control. When combined with peripheral immunization the mean area of pre-established tumors was further decreased. The effect on tumor was coupled to an increase of tumor-infiltrating T cells. In conclusion this thesis points to a synergistic effect of intratumorally located MSCs and peripheral immunotherapy with IFNγ-producing tumor cells. Hopefully this combination might be further developed into a clinically useful treatment strategy.
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| 6. |
- Marques, Catarina, 1969-
(författare)
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Studies on Cervical Artificial Disc Replacement
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Artificial disc replacement (ADR) was developed as an alternative to anterior fusion after decompression for cervical degenerative radiculopathy. By preserving motion, it was expected to prevent acceleration of adjacent segment pathology (ASP) associated with fusion, and lead to better clinical outcomes. The aims of this thesis were to evaluate whether ADR surgery leads to better outcomes than fusion surgery, to investigate if it prevents the acceleration of ASP, and to analyze its potential complications. In a multicenter randomized controlled trial (RCT) 153 patients were randomized to ADR (DiscoverTM implant) or fusion surgery (autograft, plate and screws). The outcomes at 5 and 10 years postoperatively were analyzed with Neck Disability Index (NDI) as primary measure. Heterotopic ossification (HO), ASP, and secondary surgery where analyzed. The measurements of radiographic parameters used in the assessment of cervical alignment where validated.To further analyze secondary surgery after ADR, a descriptive register cohort study was done with 42 patients whose data were retrieved from Swespine and completed with medical charts, images, and a telephone interview. There was no difference in NDI scores between groups in the RCT, 5 or 10 years postoperatively. Radiological and clinically significant ASP were similar in both groups. There was more secondary surgery in the ADR group compared with the fusion group, mainly due to device loosening in women. Severe HO was seen in 71% of the ADR implants 5 years postoperatively, and 27% were fused, male sex being a clear risk factor.Normative data for measurement error were provided on the cervical alignment measurements, and the most reliable were the K-line tilt and the cervical sagittal vertical axis (cSVA). In the 42 patients in the register cohort study the most common diagnosis leading to reoperation was loosening of the ADR implant and/or ASP, predominantly treated with fusion surgery. Reoperation resulted in good outcomes in the vast majority of patients. At the long-term, there is no clinical benefit of ADR over fusion surgery after decompression for cervical degenerative radiculopathy. ADR, compared with fusion surgery, does not prevent acceleration of ASP, and results in more reoperations. Revision surgery for failed cervical ADRs is effective and justified.
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| 7. |
- Skoog, Johan
(författare)
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Cardiovascular regulation in women with vasovagal syncope : With special reference to the venous system
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Although vasovagal syncope (VVS) is a common clinical condition the mechanisms behind VVS remain elusive. Upright posture is the major trigger of VVS and lower limb blood pooling affecting cardiac output has been proposed as a major determinant. The overall aim of this thesis was twofold. First, to develop new methodology for calculating limb venous compliance. Second, to study lower limb venous volume load and cardiovascular responses during hypovolemic circulatory stress caused by lower body negative pressure (LBNP) in healthy women and women with VVS, emphasizing compensatory mechanisms to maintain central blood volume.Net fluid filtration was associated with an underestimation ofvenous compliance. This could be accounted for with a correctionmodel. Further, a new venous wall model made it possible to adopt thevenous pressure-volume curve through the entire pressure range andthus provide a valid characterization of venous compliance.Calf blood pooling was similar between the groups and was not associated with tolerance to hypovolemic circulatory stress. Venous compliance was reduced at low venous pressures in VVS and correlated with decreased tolerance to circulatory stress. VVS women displayed attenuated sympathetic vasoconstrictor responses during graded circulatory stress, and mobilization of arm capacitance blood as well as capillary fluid absorption from extra- to intravascular space were reduced. Accordingly, more pronounced reductions in cardiac output were found in VVS. Thus, reduced compensatory mechanisms to maintain cardiac output could contribute to the pathogenesis oforthostatic VVS.In healthy women, rapid pooling in the lower limb was associated with higher tolerance to circulatory stress and more efficient cardiovascular responses, in part due to speed-dependent baroreflex-mediated sympathetic activation. In VVS however, rapid lower limb blood pooling was associated with lower tolerance and deficient cardiovascular responses. No speed-dependent baroreflexmediated sympathetic activation was found in VVS, indicating welldefined differences in cardiovascular regulation already in the initial responses to orthostatic stress.
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| 8. |
- Arvidsson, Sandra, 1986-
(författare)
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Cardiac function in hereditary transthyretin amyloidosis : an echocardiographic study
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Hereditary transthyretin amyloidosis (ATTR) is a lethal disease in which misfolded transthyretin (TTR) proteins accumulate as insoluble aggregates in tissues throughout the body. A common mutation is the exchange of valine to methionine at place 30 (TTR V30M), a form endemically found in the northern parts of Sweden. The main treatment option for ATTR amyloidosis is liver transplantation as the procedure halts production of mutated transthyretin. The disease is associated with marked phenotypic diversity ranging from predominant cardiac complications to pure neuropathy. Two different types of fibril composition – one in which both fragmented and full-length TTR are present (type A) and one consisting of only full-length TTR (type B) have been suggested to account for some phenotypic differences. Cardiac amyloidosis is associated with increased myocardial thickness and the disease could easily be mistaken for other entities characterised by myocardial thickening, such as sarcomeric hypertrophic cardiomyopathy (HCM). The aims in this thesis were to investigate echocardiographic characteristics in Swedish ATTR amyloidosis patients, and to identify markers aiding in differentiating ATTR heart disease from HCM. Another objective was to examine the impact of fibril composition and sex on the phenotypic variation in amyloid heart disease.Methods: A total of 122 ATTR amyloidosis patients that had undergone thorough echocardiographic examinations were included in the studies. Analyses of ventricular geometry as well as assessment of systolic and diastolic function were performed, using both conventional echocardiographic methods and speckle tracking technique. ECG analysis was conducted in study I, allowing measurement of QRS voltage. In study I and study II ATTR patients were compared to patients with HCM. In addition, 30 healthy controls were added to study II.Results: When parameters from ECG and echocardiography were investigated, the results revealed that the combination of QRS voltage <30 mm (<3 mV) and an interventricular/posterior wall thickness quotient <1.6 could differentiate cardiac ATTR amyloidosis from HCM. Differences in degree of right ventricular involvement were also demonstrated between HCM and ATTR amyloidosis, where ATTR patients displayed a right ventricular apical sparing pattern whereas the inverse pattern was found in HCM. Analysis of fibril composition revealed increased LV wall thickness in type A patients compared to type B, but in addition type A women displayed both lower myocardial thickness and more preserved systolic function as compared to type A males. When cardiac geometry and function were evaluated pre and post liver transplantation in type A and B patients, significant deterioration was detected in type A but not in type B patients after liver transplantation.Conclusions: Increasing awareness of typical cardiac amyloidotic signs by echocardiography is important to reduce the risk of delayed diagnosis. Our classification model based on ECG and echocardiography could aid in differentiating ATTR amyloidosis from HCM. Furthermore, the apical sparing pattern found in the right ventricle may pose another clue for amyloid heart disease, although it requires to be studied further. Furthermore, we disclosed that type A fibrils, male sex and increasing age were important determinants of increased myocardial thickness. As type A fibril patients displayed rapid cardiac deterioration after liver transplantation other treatment options should probably be sought for this group of patients.
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| 9. |
- Flondell-Sité, Despina
(författare)
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Circulating biomarkers in patients with abdominal aortic aneurysm
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Abdominal aortic aneurysm (AAA) develops in 3-6% of the population over 65 years and affects mainly men. AAA has a complex etiology involving inflammation, proteolysis, fibrinolysis and coagulation. The general aim of the present thesis was to study the associations between markers of inflammation, proteolysis, fibrinolysis and coagulation with aneurysm size and growth. In paper I associations between markers for these mechanisms and AAA size were evaluated. Patients with AAA had significantly increased levels of several markers ([endothelin] ET-1, [interleukin] IL-6, [tumour necrosis factor] TNF-α, APC-PCI) compared to age matched healthy controls. Correlations existed between aneurysm size, decreased platelet count, increased high sensitive-C-reactive protein, IL-6 and APC-PCI complex levels. In paper II effects of statin treatment were investigated, showing that patients on statins had lower levels of cholesterol, but also of homocysteine, ceruloplasmin, orosomucoid, (matrix metallo-proteinase) MMP-9 and ET-1 in plasma, but higher levels of albumin, and the APC-PCI complex. In paper III relationships between markers of proteolysis, fibrinolysis and coagulation and aneurysm size and growth during follow-up were studied. MMP-2 levels were lower in AAA patients than in healthy controls. Only MMP-2 was related to AAA size. In paper IV relationships between markers of inflammation and endothelial function and aneurysm growth were studied. We confirmed that initial aneurysm diameter is related to yearly AAA growth. Furthermore, age and initial levels of ET-1 were also related to AAA growth during 7 years follow-up. In paper V patterns of systemic biomarkers and their relationship to aneurysm growth during yearly follow-up of patients with AAA were analyzed. Few relationships were demonstrated between the development of mediators and aneurysm growth during annual analysis of this patient material, which was extended compared to the previous analyses. In conclusion, none of the above biomarkers can predict aneurysm growth or replace ultrasound surveillance.
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| 10. |
- Iosif, Robert
(författare)
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Factors Regulating Neurogenesis in Intact and Pathological Brain: Role of TNF-alpha
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- During the last decade it has been clearly demonstrated that the adult brain contains neural stem cells (NSCs) localized mainly in two regions: the subgranular zone in the dentate gyrus and the subventricular zone (SVZ) lining the lateral ventricles. In the intact brain, these NSCs give rise to new dentate granule cells and olfactory bulb neurons, respectively. Following a brain damage such as stroke and an epileptic seizure, the generation of new neurons (neurogenesis) in the hippocampus and the SVZ in adult rats, mice and probably humans is increased. The molecular mechanisms regulating the different steps of insult-induced neurogenesis (cell proliferation, survival, migration, and differentiation) are poorly understood. To learn more about the molecular mechanisms regulating neurogenesis we examined which factors in the epileptic and stroke generated environment that affects the newly formed neurons. In this thesis we explored the role of a prostaglandin and a cytokine in the hippocampus and subventricular zone, both during physiological conditions and after an insult. In the first paper we induced status epilepticus (SE) in rats by electrical stimulation in the hippocampus. We then compared the two different seizure grades, partial status epilepticus (pSE) and generalized status epilepticus (gSE), in order to identify factors in the microenvironment which are differentially regulated by SE severity and may underlie differences in neurogenesis. We particularly addressed the question whether SE severity differentially affects the expression of prostaglandin E2 (PGE2), cyclooxygenase (COX-2), the enzyme catalyzing the first committed step in PGE2 synthesis, and the brain-derived neurotrophic factor (BDNF). In conclusion, the results from paper I showed clear differences between pSE and gSE rats in hippocampal PGE2 and BDNF levels 7 days after SE. We found no evidence that the high levels of PGE2 and BDNF, in rats exhibiting pSE, during the first days after SE are of major importance for the survival of new neurons during the first days after formation. In the second study, we developed a new SE model for mice based on continuous electrical stimulation in the hippocampus, as done previously in rats. We then investigated whether the cytokine, tumor necrosis factor alpha (TNF-α), could influence neurogenesis. TNF-α is a well-known proinflammatory factor and we speculated that the detrimental action of inflammation on insult-induced neurogenesis might be caused by TNF-α. It had also been shown that NSCs themselves express TNF-α, which raised the possibility of an autocrine action involved in neurogenesis. We used transgenic mice with various genetic manipulations of TNF-α signaling to determine the influences on neurogenesis under physiological conditions and following a brain insult. Taken together, the results from paper II demonstrate the involvement of TNF-R1 and TNF-R2 signaling in the regulation of adult hippocampal neurogenesis, and that signaling through the two different receptors have differential actions on neurogenesis. Our data indicate that TNF-α can modulate the formation of new neurons both under physiological and pathological conditions by acting on these two receptors with differential effects on proliferation and survival, with TNF-R1 as the key mediator of TNF-α signaling. In the final study we examined whether signaling through TNF-R1 could influence progenitor proliferation in another neurogenic area during physiological conditions and following a pathological condition such as stroke and SE. We used the same transgenic mice to study TNF-α and its effects on the formation of new neurons in the SVZ. We found that mice lacking TNF-R1 function responded to stroke with enhanced SVZ cell proliferation and thereby that TNF-R1 signaling mediates a suppressant effect on the proliferation of progenitor cells. Following stroke TNF-R1 acts as a negative regulator on the progenitor proliferation. In contrast, deletion of TNF-R1 did not influence basal cell proliferation in SVZ. Further, loss of TNF-R1 function had differential effects on SVZ cell proliferation following the two pathological conditions SE and stroke and we did not find any differences in cell proliferation after SE. Although both insults gave rise to increased cell proliferation in the SVZ, the dampening action of TNF-R1 on proliferation was revealed only after stroke. Taken together, the results from paper II and III suggest that suppression of TNF-R1 signaling might be a strategy to promote the proliferative response in the SGZ after SE and in the SVZ after stroke, to stimulate neurogenesis in the adult brain. However, it will be important to establish how such an approach will affect other steps of neurogenesis and the functional outcome after both SE and stroke. There could be a positive therapeutic potential of neurogenesis from endogenous stem cells after brain insults. However, we need to know much more about the regulation of neurogenesis in order to make this response more effective. The current thesis work aims at elucidating some of the mechanisms of neuronal self-repair, which could have implications for the development of stem cell-based approaches for the treatment of brain disorders.
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