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Pak hip osteonecrosis knee osteoarthritis autologous adipose-derived stem cells j med case rep 201

Pak Journal of Medical Case Reports 2011, 5:296http://www.jmedicalcasereports.com/content/5/1/296 JOURNAL OF MEDICAL Regeneration of human bones in hip osteonecrosisand human cartilage in knee osteoarthritis withautologous adipose-tissue-derived stem cells:a case series Introduction: This is a series of clinical case reports demonstrating that a combination of percutaneously injectedautologous adipose-tissue-derived stem cells, hyaluronic acid, platelet rich plasma and calcium chloride may beable to regenerate bones in human osteonecrosis, and with addition of a very low dose of dexamethasone,cartilage in human knee osteoarthritis.
Case reports: Stem cells were obtained from adipose tissue of abdominal origin by digesting lipoaspirate tissuewith collagenase. These stem cells, along with hyaluronic acid, platelet rich plasma and calcium chloride, wereinjected into the right hip of a 29-year-old Korean woman and a 47-year-old Korean man. They both had a historyof right hip osteonecrosis of the femoral head. For cartilage regeneration, a 70-year-old Korean woman and a79-year-old Korean woman, both with a long history of knee pain due to osteoarthritis, were injected with stemcells along with hyaluronic acid, platelet rich plasma, calcium chloride and a nanogram dose of dexamethasone.
Pre-treatment and post-treatment MRI scans, physical therapy, and pain score data were then analyzed.
Conclusions: The MRI data for all the patients in this series showed significant positive changes. Probable boneformation was clear in the patients with osteonecrosis, and cartilage regeneration in the patients withosteoarthritis. Along with MRI evidence, the measured physical therapy outcomes, subjective pain, and functionalstatus all improved. Autologous mesenchymal stem cell injection, in conjunction with hyaluronic acid, platelet richplasma and calcium chloride, is a promising minimally invasive therapy for osteonecrosis of femoral head and, withlow-dose dexamethasone, for osteoarthritis of human knees.
differentiate into bones, cartilage, muscle and adipose Adipose-tissue-derived stem cells (ADSCs) have been tissue, representing a promising new area of therapy in widely used in Korea over the last few years by plastic regenerative medicine surgeons as a semi-permanent volume expander. In June Because of their potent capabilities, MSCs have been 2009, the Korean Food and Drug Administration used successfully in animal models to regenerate carti- (KFDA) allowed ADSCs to be used as autologous cell lage and bones In 2008, Centeno and colleagues transplant when obtained and processed within a medi- reported regeneration of knee cartilage in a human by cal clinic with minimal processing using autologous culture-expanded bone-marrow- Mesenchymal stem cells (MSCs) are found in numer- derived stem cells However, to the best of our ous human tissues including bone marrow, synovial knowledge ADSCs have never been used successfully in tissue and adipose tissue. These have been shown to osteonecrosis of a femoral head and in osteoarthritis ofa human knee.
Osteonecrosis, or avascular necrosis, of femoral head is relatively a common disorder affecting individuals in Miplant Stems Clinic, 32-3 Chungdam-Dong, Gangnam-Gu, Fourth Floor, their 30s to 50s. Osteoarthritis of a knee is an even 2011 Pak; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License ), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.
Pak Journal of Medical Case Reports 2011, 5:296 more common disorder, especially in older patients.
treatment of the disease, she elected to receive stem cell Currently, the only cure for both diseases is surgical intervention. However, the successful regeneration of At the time of initial evaluation, she reported moder- bones and cartilage with ADSCs may represent a pro- ately severe pain (visual analog scale (VAS) score 7) on mising new, minimally invasive, non-surgical alternative.
rest, increased pain when standing and walking (VAS Many issues need to be resolved and clarified before the general application of the procedure. The mechan- For a week prior to liposuction, she was restricted ism of regeneration is not yet clear. It could be through from taking corticosteroids, aspirin, NSAIDs, and orien- direct differentiation of stem cells that were introduced tal herb medications.
to the diseased joints. Alternatively, it could be due to For the liposuction procedure, she was brought into the tropic effects of ADSCs on the existing tissues.
an operating room and placed in a supine position. She Further, various elements of the local environment can was then sedated with propofol 2 mg intravenously affect the differentiation of MSCs Also, it is believed (push) and a 20 mg/hour rate of continuous infusion.
that a scaffolding material might be needed to allow the After cleaning her abdominal area with povodine- MSCs to attach and engraft iodine and placing sterile drapes, an incision of approxi- Platelet-rich plasma (PRP) was used as a growth factor mately 0.5 cm was made approximately 5 cm below the and as a differentiating agent for the MSCs. PRP con- umbilicus. Then, using tumescent solution (500 cm3 tains multiple growth factors including transforming normal saline, 40 cm3 2% lidocaine, 20 cm3 0.5% mar- growth factor (TGF)b, insulin-like growth factor (IGF), caine, 0.5 cm3 epinephrine 1:1000), the lower abdomen fibroblast growth factor (FGF), and platelet-derived area was anesthetized. Next, using a 3.0 Hartman can- growth factor (PDGF). A literature review of the data on nula, a total of 160 cm3 of lipoaspirates were extracted PRP shows that it has a positive effect on the stimula- and separated by gravity. The resulting 100 cm3 of adi- tion of bones, blood vessel and chondrocyte formation pose tissue was then centrifuged at 3500 rpm for five Hyaluronic acid was added as a scaffolding mate- minutes. The end result was approximately 40 cm3 of rial, and calcium chloride was used as a PRP-activating packed adipose tissue, fibrous tissue, red blood cells and a small number of nucleated cells.
This series of case reports demonstrates successful An equal volume of digestive enzyme, 0.07% collage- clinical results of regenerating bones in osteonecrosis nase type 1, composed of several collagenases, sulfhydryl and cartilage in patients with osteoarthritis, using percu- protease, clostripain, a trypsin-like enzyme, and a amino taneously implanted, autologous MSCs along with PRP, peptidase, derived from Clostridium histolyticum (Adi- hyaluronic acid, calcium chloride (CaCl2) and very-low- lase; Worthington, Lakewood, NJ, USA) was then mixed dose dexamethasone.
with the centrifuged lipoaspirates at a ratio of 1:1 anddigested for 30 minutes at 37°C while rotating Case presentations Bacterial collagenases differ from vertebrate collage- The following cases concern four different individuals.
nases in that they exhibit broader substrate specificity Of the four, the first two cases involve bone regenera- tion in osteonecrosis of hips, the latter two cases regen- After the digestion, the lipoaspirates were centrifuged at eration of cartilage in osteoarthritis of knees.
100g for three minutes to separate the lipoaspirate and The first case concerns a 29-year-old Korean woman the enzyme. The leftover enzyme was then removed.
with over a year's history of right hip pain due to Using 500 cm3 5% dextrose in lactated Ringer's solu- tion, the lipoaspirates were washed three times to Approximately a year prior to presentation, she started remove the collagenase. After each washing, the lipoas- having hip pain with no history of trauma. She was seen pirates were centrifuged at 100 g. After the last centri- by a physician and was diagnosed with osteoarthritis of fuge process, approximately 10 cm3 of ADSCs were the hip after an MRI scan. After taking non-steroidal anti-inflammatory drugs (NSAIDs) for a few weeks, her While preparing the ADSCs, 30 cm3 of autologous hip pain improved. About a month prior to presenta- blood was drawn with 2.5 cm3 of anticoagulant citrate tion, she again started having hip pain radiating to the dextrose solution (ACD) formula. This was centrifuged anterior region of the right knee. The pain was worse at 200 g for five minutes. The resultant supernatant was when standing up, walking, and exercising. The pain drawn and centrifuged at 1000 g for five minutes. The improved with rest. However, this time, the pain was supernatant was drawn and discarded. The resulting not greatly relieved with NSAIDs.
buffy coat was mixed with 10 cm3 of ADSCs.
A repeat MRI showed osteonecrosis of the femoral Hyaluronic acid 1 cm3 was added to this mixture to head, stage 4. Since there is no effective non-surgical act as a scaffold. This PRP was again mixed with CaCl2 Pak Journal of Medical Case Reports 2011, 5:296 for activation of platelets at a ratio of 10:2 (PRP 10:2 The third case concerns a 70-year-old Korean woman with over five years' history of right knee pain due to In order to inject the mixture of stem cells and PRP, our patient was first placed in a lateral position with her Due to her occupation, she made active use of her bilat- left side down. After cleaning with povodine-iodine and eral knee joints. With a diagnosis of osteoarthritis of the draping with sterile drapes, 2% lidocaine was used to right knee, she had received multiple injections of steroids anesthetize the hip at the femoral head region. Using a and hyaluronic acid over the years. However, she did not 22-gauge 3.5-inch needle, 17 cm3 mixture of ADSCs, notice any improvement in her pain. She was seen by an PRP, hyaluronic acid and CaCl2 were injected into the orthopedic surgeon and was offered a total knee replace- femoral head under ultrasound guidance.
ment (TKR). She was reluctant to go through the TKR She was then instructed to remain still with her leg procedure due to possible side effects. Since then, she has elevated for 30 minutes to allow for cell attachment. On been receiving physical therapy with little improvement.
discharge home, she was instructed to maintain activity At the time of initial evaluation, she reported moder- as tolerated. She returned to the clinic for four addi- ately severe pain (VAS score 7) on rest. Her knee pain tional PRP injections with calcium chloride every week increased when walking. She also complained of mild over a period of a month.
knee swelling. On physical examination, there was mild After the fourth week of the ADSC injection, her pain joint swelling, a decreased range of motion and tender- had improved more than 50%. By week 12, her pain had ness with flexion. Apley and McMurray tests were nega- improved more than 70% along with an improvement in tive, and there was no ligament laxity.
range of motion (Tables and . A repeat MRI taken A pre-treatment 1.5T MRI scan demonstrated a at week 12 showed a significant filling of bone defects decreased size and deformed contour on the medial on the superior acetabulum and probable bone matrix meniscus of the left knee due to maceration.
formation in the subcortical region of the femoral head After obtaining ADSCs and preparing PRP as described above for the first two patients, she was prepared for The second case concerns a 47-year-old Korean man injection of the mixture into the joint.
who had been working as a diver until three years prior In order to inject the stem cell and PRP mixture, she to presentation.
was first placed in a supine position with her right knee Approximately three years prior to presentation, he bent at 90°. After cleaning with povodine-iodine and started having right hip pain and was diagnosed with draping with sterile drapes, her knee was anesthetized osteonecrosis of the right hip. His pain had progressed with 2% lidocaine at the medial and lateral sides of the over three years and he was offered a total hip replace- inferior patella. Using a 22-gauge 1-inch needle, 8.5 cm3 ment (THR). Being reluctant to proceed with the surgi- of ADSCs, PRP, dexamethasone and hyaluronic acid cal procedure, he elected to proceed with stem cell mixture was injected into the medial and the lateral treatment. Before the procedure, a repeat MRI of the sides of the knee.
hip was performed and a diagnosis of osteonecrosis of She was then instructed to remain still for 30 minutes the femoral head, stage 4, was confirmed.
to allow for cell attachment. As she was subsequently He then underwent the same procedures as our first discharged from the clinic, she was instructed to main- patient. After the fourth week of the ADSC injection, tain activity as tolerable.
his pain improved more than 30% along with improve- She returned to our clinic for four additional PRP and ment in range of motion. However, by week 12, his pain dexamethasone injections over the next four weeks.
had only minimally improved further (Tables and After the seventh week of ADSC injection, her pain had Interestingly, a repeat MRI taken at week 12 showed a improved more than 80% and flexion of the knee had significant filling of bone defects with a possibility of also improved. By week 12, her pain had improved bone matrix formation at the site of necrosis in the more than 90% and the range of motion also further femoral head (Figure improved (Tables and . A post-treatment MRI takenat week 12 showed a significant increase in the thicknessof meniscus cartilage on the medial side of the right Table 1 Functional rating index and visual analog knee (Figures and scale (VAS) score for patient 1 The final case concerns a 79-year-old Korean woman with over seven years' history of bilateral knee pain due injection treatment follow-up treatment follow-up to osteoarthritis.
Her left knee was much more painful than the right.
Due to her occupation, she made active use of her bilat- eral knee joints. With a diagnosis of osteoarthritis of Pak Journal of Medical Case Reports 2011, 5:296 Table 2 Physical therapy (PT) range of motion of patient 1 Pre-injection evaluation four weeks post-treatment follow- 12 weeks post-treatment follow-up 125 VAS = visual analog scale.
both knees, she had received multiple injections of ster- decreased range of motion and tenderness with flexion.
oids and hyaluronic acid in both knees over the years.
Apley and McMurray tests were negative, and there was However, she noticed no improvement of pain. She was no ligamentous laxity.
seen by an orthopedic surgeon and was offered a TKR.
A pre-treatment 1.5T MRI demonstrated a decreased She was also reluctant to go through the TKR due to size and deformed contour on her medial meniscus of possible side effects. Since then, she had been receiving the left knee due to maceration. She also underwent the physical therapy with little improvement.
same procedure as our previous patient.
At the time of initial evaluation, she reported severe After the fourth week of ADSC injection, her pain pain in the left knee (VAS score 8) on rest. The pain improved over 50% and flexion of the knee improved as was increased when walking. On physical examination, well. By week 12, her pain had improved over 90% and there was deformity of the knee, mild joint swelling, a she was able to flex her knee further (Tables and Figure 1 MRI of the right hip; T1 sequential coronal views. The cavity surrounded by the three green arrows has decreased in size in post-treatment MRIs due to probable bone regeneration.
Pak Journal of Medical Case Reports 2011, 5:296 Table 3 Functional rating index and visual analog scale (VAS) score of patient 2 four weeks post-treatment follow-up 12 weeks post-treatment follow-up Functional rating index Table 4 Physical therapy (PT) range of motion of patient 2 Pre-injection evaluation four weeks post-treatment follow- 12 weeks post-treatment follow-up 105 VAS = visual analog scale.
Figure 2 MRI of the right hip; T1 sequential coronal views. The blue arrow shows the pattern of probable bone regeneration. The greenarrow shows probable bone consolidation.
Table 5 Functional rating index and visual analog scale (VAS) score of patient 3 seven weeks post-treatment follow-up 12 weeks post-treatment follow-up Functional rating index Pak Journal of Medical Case Reports 2011, 5:296 Table 6 Physical therapy (PT), range of motion of patient 3 Flexion (degrees) Extension (degrees) Pre-injection evaluation seven weeks post-treatment follow-up 12 weeks post-treatment follow-up VAS = visual analog scale.
A repeat MRI taken at week 12 showed a significantincrease in the height of her meniscus cartilage on theanterior medial side of the left knee (Figures and DiscussionThis series of clinical case reports provides clear MRI evi-dence of apparent bone regeneration in osteonecrosis offemoral heads and meniscus cartilage regeneration inosteoarthritis of human knees. Based on the MRI features,it is probable that the new tissue formation is bone matrixin the case of osteonecrosis and meniscus cartilage inosteoarthritis. However, without biopsy, the true nature ofthe newly-formed tissue is unclear. While bone and carti-lage regeneration using ADSCs has been shown in animalmodels, these case reports represent the first successfulregeneration of bones and cartilage in human patients.
In addition to the MRI evidence, the patients' symp- Figure 3 MRI sagittal T2 view of the knee. Pre-treatment and toms and signs also improved. It is worthwhile to note post-treatment MRI shows increased height of medial meniscus that the patients cartilage and articular cartilage (arrow).
' symptoms improved gradually over three months. Thus, it can be speculated that, inpatients with osteonecrosis, newly-formed bone has con-comitant neovascularization. Osteonecrosis, or avascularnecrosis, occurs due to compromise in blood circulation.
Without concurrent neovascularization, the consolida-tion or regeneration of bones cannot be sustained.
Figure 4 MRI coronal T2 view of the knee. Pre-treatment andpost-treatment MRI shows increased height of medial meniscus(arrow).
Table 7 Functional rating index and visual analog scale(VAS) score of patient 4 injection treatment follow-up treatment follow-up Figure 5 MRI sagittal T2 view of the knee. Pre-treatment and post-treatment MRI shows increased height of medial meniscus cartilage. The articular cartilage also has a clearer marking, representing probable cartilage regeneration.
Pak Journal of Medical Case Reports 2011, 5:296 Further, dexamethasone injection, used as a differen- tiating agent for cartilage, may also have had positiveeffects in patients with osteoarthritis. The levels injected(100 ng/mL) were negligible compared to the dosesbeing used in clinical settings. Such low doses in thenanogram range have been shown to increase extracellu-lar matrix production by chondrocytes, and are com-monly used in vitro to differentiate MSC from cartilage This is the first series of case reports showing possible successful bone and cartilage regeneration in humans byusing a combination of ADSCs, hyaluronic acid, PRPand CaCl2. Currently, no non-surgical therapy is avail-able for the treatment of osteonecrosis and osteoarthri-tis. Thus, stem cell therapy may significantly improve Figure 6 MRI coronal T2 view of the knee. The anterior medial current treatment strategies for the treatment of knee meniscus has increased in height.
osteoarthritis and osteonecrosis of the femoral head.
However, further studies need to be initiated to find outthe true detailed nature of the apparently regenerated Another issue with these clinical results is that bones and cartilage and to determine the true mechan- patients with osteoarthritis did not report 100% symp- ism of tissue regeneration.
tom improvements. This may be due to the fact thatosteoarthritis is a disease of the whole knee, not just the After three months of treatment, all the patients With regard to the mechanism of tissue regeneration, reported on above were able to straighten their hips and there are a few plausible possibilities. The mechanism of extend their knees further, affecting MRI postures.
regeneration could be through direct differentiation of Therefore, obtaining the post-treatment MRI data at the stem cells that were introduced through the injection.
exactly same location as pre-treatment MRI of the hips However, there is a possibility that the ADSCs exert tro- and knees was difficult.
pic effects on the existing tissues as well. Numerous stu- Although there were difficulties in repeatedly obtaining dies have reported that MSCs, in addition to tissue the exact location of the hips and knees, the pre-proce- repair and regenerative effects, have immunomodulatory dure and post-procedure MRI analyses clearly demon- and paracrine effects strate filled bone defects in osteonecrosis and increased Furthermore, PRP could have contributed to the regen- meniscus cartilage volume in osteoarthritis, indicating eration of bones and blood vessels. PRP contains multiple regeneration attributable to the ADSC treatment. Addi- growth factors including TGFb, IGF, FGF, and PDGF. A tionally, the measured physical therapy outcomes, subjec- literature review of the data on the uses of PRP showed tive pain, and functional status, all improved that it has a positive effect on the stimulation of bones andblood vessels and chondrocytes. Here, it was used as a growth factor and as a differentiating agent for the MSCs.
Written informed consent was obtained from allpatients for publication of this case report and any Table 8 Physical therapy (PT) range of motion of patient accompanying images. Copies of the written consents are available for review by the Editor-in-Chief of this JP acknowledges the support from the staff of Miplant Stems Clinic.
Authors' contributions JP was in charge of patient treatment and follow-up, was responsible formanuscript drafting and revision, and read and approved the final Competing interests VAS = visual analog scale.
The authors declare that they have no competing interests.
Pak Journal of Medical Case Reports 2011, 5:296 Received: 11 October 2010 Accepted: 7 July 2011 Published: 7 July 2011 Korean Food and Drug Administration: Cell therapy. Korean Food and DrugAdministration Rules and Regulations Seoul, Korea: Food and DrugAdministration;, Chapter 2, Section 12.
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doi:10.1186/1752-1947-5-296Cite this article as: Pak: Regeneration of human bones in hiposteonecrosis and human cartilage in knee osteoarthritis with autologousadipose-tissue-derived stem cells: a case series. Journal of Medical CaseReports 2011 5:296.
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