Knee joint preservation with combined neutralising high tibial osteotomy (HTO) and Matrix-induced Autologous Chondrocyte Implantation (MACI) in younger patients with medial knee osteoarthritis: a case series with prospective clinical and MRI follow-up over 5 years.

PURPOSE: There is no ideal treatment for younger patients with medial knee osteoarthritis (OA) and varus malalignment. We have investigated the first case series of combined neutralising high tibial osteotomy (HTO) and Matrix-induced Autologous Chondrocyte Implantation (MACI) with MRI. Treatment goals were clinical improvement and delay of arthroplasty. METHODS: Between 2002 and 2005 18 patients (Mean age 47 years) underwent surgery. Exclusion criteria were lateral compartment and advanced patellofemoral OA. The Knee Injury and Osteoarthritis Outcome Score (KOOS), six minute walk test (6MWT) and a validated MRI score were outcome measures. RESULTS: There were significant improvements (p<0.05) in all five KOOS domains. Four were significantly maintained to 5 years. The domain "symptoms" and results in the 6MWT dropped off at 5 years. MRI results were first significantly improved (24/12) but declined at 60 months. Good quality infill was found in 33% patients at the study endpoint (n=5/15). Histological investigation of one knee demonstrated full-thickness hyaline-like cartilage (20/12). After 2 early failures and one graft detachment graft fixation was changed (Smart nails instead of sutures in 14 cases). Graft hypertrophy requiring a chondroplasty occurred once. There were no other major complications. Specific minor complications included patellar tendinitis (n=8). CONCLUSIONS: This combined procedure provides a safe treatment option for younger patients with medial knee OA and varus alignment with significant clinical improvement at 5 years. However, overall graft survival and cartilage infill were poor. Larger studies are needed to statistically verify predictors for longer term cartilage repair in these patients.

Traditional vs accelerated approaches to post-operative rehabilitation following matrix-induced autologous chondrocyte implantation (MACI): comparison of clinical, biomechanical and radiographic outcomes.

OBJECTIVE: To determine the effectiveness of 'accelerated' compared to 'traditional' post-operative load bearing rehabilitation protocols following matrix-induced autologous chondrocyte implantation (MACI). METHOD: A randomized controlled study design was used to investigate clinical, biomechanical and radiographic assessment at 3 months post-surgery in 62 patients following MACI to the medial or lateral femoral condyle. Both rehabilitation interventions sought to protect the implant for an initial period, then incrementally increase load bearing. Under the 'accelerated' protocol, patients reached full weight bearing at 8 weeks post-surgery, compared to 11 weeks for the 'traditional' group. RESULTS: Patients in the 'accelerated' group achieved greater 6 min walk distances and daily activity levels as measured by accelerometry (P<0.05) compared to the 'traditional' group. Furthermore, the 'accelerated' group reported significantly better improvement in knee pain at 12 weeks as indicated by the Knee Injury and Osteoarthritis Outcome Score (P<0.05), and regardless of the rehabilitation protocol employed, no patient suffered any adverse effect to the implant as assessed by magnetic resonance imaging at 3 months. Comparison of each rehabilitation group with an unaffected control group revealed a significant difference in peak knee adduction and flexion moments for the traditional group (P<0.05). However, there was no difference for accelerated patients (P>0.05), which may demonstrate a faster return to knee loading patterns typically observed in unaffected subjects. CONCLUSION: The 'accelerated' load bearing approach that reduced the length of time spent ambulating on crutches resulted in reduced knee pain, improved function, no graft complications and may speed up the recovery of normal gait function. Patient follow-up to at least 24 months would be required to observe longer-term graft outcomes.

MRI and clinical evaluation of collagen-covered autologous chondrocyte implantation (CACI) at two years.

We present our experience with the collagen-covered autologous chondrocyte implantation (CACI) technique. Thirty two implantations were performed in 31 patients. Clinical outcome was measured using the KOOS score and the 6-minute walk test, as well as an MRI scoring protocol (75% of patients had a complete data set for MRI follow-up) to describe the repair tissue generated by CACI. We have also correlated our MRI results with our clinical outcome. To the authors knowledge there are no comparative studies of MRI and clinical outcome following CACI in the current literature. Patients demonstrated an increased walk distance that improved significantly from 3 months to 24 months postoperatively (p<0.05). Analysis of the KOOS results demonstrated a significant (p<0.05) improvement in four of the five subscales from 3 months to 24 months after CACI, with the most substantial gains made in the first 12 months. Patients demonstrated an increased MRI outcome score over time that improved significantly from 3 months to 24 months postoperatively (p<0.05). We observed an 8% incidence of hypertrophic growth following CACI. We report one partial graft failure, defined by clinical, MRI and histological evaluation, at the one year time point. In contrast to the current literature we report no incidence of manipulation under anesthesia (MUA) following CACI. This research demonstrates that autologous chondrocytes implanted under a type I/III collagen patch regenerates a functional infill material, and as a result of this procedure, patients experienced improved knee function and MRI scores. Whilst our results indicated a statistically significant relationship between the MRI and functional outcome following CACI, MRI cannot be used as surrogate measure of functional outcome following CACI, since the degree of association was only low to moderate. That is, functional outcome following CACI cannot be predicted by the morphological MRI assessment of the repair tissue at the post-surgery time points to 24 months.

Acute atherosis in preeclampsia: maternal determinants and fetal outcome in the presence of the lesion.

In 39 patients with preeclampsia a detailed analysis of some maternal factors, fetal outcome, and a histologic assessment of the presence or absence of acute atherosis in maternal intrauterine vessels has been done. There was no statistically significant relation between acute atherosis and parity, degree of proteinuria, severity and duration of hypertension, or antihypertensive therapy. These findings do not support a purely hemodynamic pathogenesis for the vasculopathy. Fetal outcome was only marginally worse in the preeclamptic patients who developed acute atherosis.

Defective haemochorial placentation as a cause of miscarriage: a preliminary study.

The morphology of the placental bed in idiopathic sporadic and recurrent miscarriages was studied and the findings correlated with the fetal chromosomal pattern where possible. Defective development of haemochorial placentation, which was not necessarily linked with fetal chromosomal abnormality, was seen in association with some miscarriages. These preliminary results, not previously demonstrated, strongly support the concept that miscarriages and pregnancies complicated by pre-eclampsia and/or small-for-gestational-age infants may be a continuum of disorders with a similar pathology in the placental bed.

Placenta creta and placenta praevia creta.

The placental bed in placenta creta and placenta praevia creta was studied from pregnancy or immediate postpartum hysterectomy specimens. In all cases placental villi were seen in direct contact with myometrium, the sine qua non of placenta creta, but was focal in some cases. There was no apparent diminution of decidua parietalis or, in cases of focal accreta, of adjacent basalis. In all cases the extravillous trophoblast was mainly uninuclear or binuclear, in contrast to the placental bed syncytial giant cells seen in late normal placentation. There was an apparent proliferation of interstitial trophoblast at the junction of placenta with myometrium, but the density of interstitial trophoblast deeper in the myometrium was lower than it is in normal placentation. An unusual uteroplacental vasculature was seen in which physiological changes were present in large arteries of the radial/arcuate system deep in the myometrium, while there were also spiral arteries more superficially without physiological changes. These findings suggest that in placenta creta there is defective interaction between maternal tissues, particularly decidua, and migratory trophoblast in the early stages of placentation resulting in undue adherence of the placenta or penetration into the uterus coupled with the development of an abnormal uteroplacental circulation.

Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational age infants.

An examination of the maternal vascular response to placentation shows that physiological changes in the placental bed normally extend from the decidua into the inner myometrium. In pre-eclampsia and in a proportion of pregnancies with small-for-gestational age infants (SGA) the physiological changes are restricted to the decidual segments alone. In addition, complete absence of physiological changes throughout the entire length of some spiral arteries is seen in pre-eclampsia and SGA. This new observation is confirmed in a study of basal plates of placentas from abnormal pregnancies. Intraluminal endovascular trophoblast may be seen in the placental bed spiral arteries in the third trimester in pre-eclampsia and SGA, a feature not seen beyond the second trimester in normal pregnancy. These findings point to a defect in the normal interaction between migratory trophoblast and maternal uterine tissues in pre-eclampsia and in SGA.

The placental bed biopsy: review from three European centers.

This review derives from extensive experience with the placental bed biopsy technique in three centers over the last 30 years. A placental bed biopsy, usually taken at cesarean section, must include basal decidua and subjacent myometrium from the central zone of the placental site. Attention is drawn specifically to the sampling errors and to the pitfalls in morphologic interpretation of tissues, both maternal and fetal, that are continuously changing throughout the course of pregnancy. The features of the normal placental bed and of vascular lesions in pathologic pregnancies are briefly reviewed. Extension and elaboration of the technique and its more widespread use could contribute to the elucidation of many of the unresolved problems in human pregnancy.

An immunocytochemical study of fetal cells at the maternal-placental interface using monoclonal antibodies to keratins, vimentin and desmin.

The expression of keratin, vimentin and desmin intermediate filaments by cells in the placenta, amniochorion and placental bed at different stages of pregnancy was studied by use of a panel of monoclonal antibodies. All trophoblast subsets express keratin but not vimentin or desmin intermediate filaments at all stages of pregnancy. Differentiation of the various forms of trophoblast probably does not involve qualitative alterations to the keratin pattern of embryonic trophoblast. Amniotic epithelium co-expressed keratin and variable amounts of vimentin while a subset of fetal mesenchyme cells of the amniochorion and chorionic villi were immunolabelled by antibodies to keratin, to vimentin and to desmin, suggesting simultaneous triple co-expression of three intermediate filaments. This finding suggests the identification of a cell population that is analogous to parietal endoderm in some eutherian animals.

Strongyloidiasis in Canadian Far East war veterans.

A survey was done of Canadians who had been interned by the Japanese during World War II to assess the prevalence of latent infection with Strongyloides stercoralis in this group. Packages containing three mail-in kits and a questionnaire were sent to 992 men, 694 (70%) of whom responded. Larvae were found in the stool specimens of four of the respondents. Examination of stool specimens after formalin-ether concentration was the most successful method of detecting Strongyloides larvae. The Baermann concentration technique yielded negative results in all four men. Three of the four cases of strongyloidiasis were detected after sampling of three fecal specimens. In the fourth case additional specimens were requested on the basis of data derived from the questionnaire. The most frequently cited clinical manifestations were abdominal pain, weight loss, diarrhea and rashes.

Human cytotrophoblast populations studied by monoclonal antibodies using single and double biotin-avidin-peroxidase immunocytochemistry.

Single and double biotin-avidin-peroxidase immunocytochemical methods in conjunction with an anti-trophoblast monoclonal antibody 18B/A5 and an anti-HLA-A,B,C monoclonal antibody W6/32 were used to study various human trophoblast populations. Several combinations of peroxidase substrates were tried in the double-labeling procedure. It was concluded that the use of 4-chloro-1 naphthol to develop the primary sequence peroxidase and of 3-amino-9-ethyl carbazole for the second sequence peroxidase was the most suitable. The significant findings were: Monoclonal antibody 18B/A5 proved to be a useful marker for villous as well as nonvillous trophoblast, which facilitated the identification of these cells particularly in the placental bed. The expression of MHC Class I antigens was not confined to extravillous trophoblast but these antigens were also demonstrable on the villous cytotrophoblast proliferating to form new primary villi. Double labeling revealed that many of these cells, particularly those furthest away from the mesenchymal core, expressed both trophoblast and HLA antigens as shown by a mixing of the colors produced by the two reaction products. A large number of these HLA-A,B,C, positive trophoblast cells were found to infiltrate deep into the uterine myometrium. The hypothesis was put forward that these fetal cells could be the ones that are responsible for maternal sensitization.

Abnormal placentation.

It is only relatively recently that attention has been directed to studies of the uterine side of the placenta to look for possible defects that might explain otherwise inexplicable pregnancy complications. Preeclampsia and intrauterine fetal growth retardation are two such disorders, in which new information has come to light by the study of placental bed biopsies and occasional cesarean hysterectomy specimens. It will be less easy to apply these techniques to such problems as spontaneous abortion and antepartum hemorrhage, but reemphasizing what should be the self-evident importance of the establishment and development of the uteroplacental blood supply might help reorient thinking about these and other important complications of pregnancy. Fresh thoughts are required too about the etiology and natural history of ectopic pregnancy, not so much for its own sake but more because of what it tells us about nidation and placentation in general. It is now difficult to insist on stringent criteria for the endometrium in human gestation, with all that this implies for the woman under investigation for infertility, when in some circumstances these criteria are flouted in what should be an alien mucosa. Much more needs to be known about the promotion and control exercised over trophoblastic differentiation and migration and interaction with uterine tissues. The uterus certainly can no longer be considered an immunologically privileged site even were that privilege extended to the fallopian tube and, indeed, to the adnexa generally. The constraining influence of decidua, if indeed it has such a property, requires elucidation; it cannot be fortuitous that only in species with hemochorial placentation, characterized by migratory nonvillous trophoblast, is a true stromal decidua formed. This surely indicates that decidua has a major role to play in negotiating "the treaty of compromise" ultimately signed between fetal and maternal tissues and if such a treaty is not signed, or is broken, defective placentation and its consequences must follow.

A reappraisal of the endometrium in infertility.

It will be obvious to the reader that the author has gone to considerable lengths to exculpate the endometrium from playing a significant role in the aetiology and pathogenesis of infertility. No apology is necessary for this approach as it is known to obstetricians and gynaecologists engaged in the management and treatment of the infertile couple that most causes of infertility have little to do directly with endometrial abnormalities. This does not mean, however, that an endometrial biopsy or curettage specimen has no place in the investigation of the infertile woman. It can be used as an adjunct to the monitoring of the efficacy of treatment for ovulatory failure and in the confirmation and typing of endometrial hyperplasia in the woman with persistent anovulatory cycles. It is virtually indispensable for the diagnosis of genital tuberculosis and as a means of culturing the mycobacterium for antibiotic sensitivity testing so that appropriate therapy can be given. While there are better methods now available, such as laparoscopy, for the diagnosis of pelvic inflammatory disease, the finding of unsuspected endometritis in the infertile woman can be used as an indicator of low-grade chronic genital tract infection that may not be otherwise apparent. There would seem to be no need for routine investigation of the endometrium in women afflicted with endometriosis or tubal disorders. The most controversial use of endometrial biopsy as an investigational technique is in the diagnosis of luteal deficiency and related disorders. If it is to be used in this circumstance, then it is essential that there should be the closest possible consultation between the clinician and the pathologist. It is too early yet to declare the endometrium always blameless in reproductive failure but there is little hope that purely morphological studies, even at the ultrastructural level, will supply answers to the unresolved questions. The investigation of the complex biochemistry and biology of the endometrium is still very much in the developmental stage. Pathologists interested in reproductive biology must be prepared to adapt and to devise new techniques based on biochemical discoveries to supplement their traditional morphological assessment of this important and fascinating tissue.

Uteroplacental arterial changes related to interstitial trophoblast migration in early human pregnancy.

Morphometric and statistical techniques were used to assess the relation of myometrial interstitial trophoblast to the uteroplacental vasculature in 27 intact hysterectomy specimens ranging from 8 to 18 weeks' gestation. It was found that the volume density of cytotrophoblast in the myometrium and in particular the proximity of such trophoblast to the placental bed spiral arteries correlated significantly with morphological alterations in these vessels. The changes included swelling of endothelium, hypertrophy of individual medial smooth muscle cells, and oedema and disruption of the architecture of the vessel wall as a time-related continuum. Some of the changes, such as swollen endothelium and basophilia of medial smooth muscle cells were noted also in spiral arteries in the non-placental bed endometrium but to a considerably less extent than in the placental bed. Intimal vacuolation was common to placental bed and non-placental bed arteries, increased with gestational age and can be considered as a non-specific feature. The migration of endovascular trophoblast into the myometrial spiral arteries in the second trimester occurred only when these arteries had been considerably altered in their morphology. These findings indicate that migratory interstitial cytotrophoblast probably has a role to play in the preparation of the myometrial segments of the uteroplacental arteries for the second wave of endovascular trophoblast migration that occurs in the second trimester of human pregnancy.

Hemolyzed blood and serum levels of delta 9-THC: effects on the performance of roadside sobriety tests.

A pilot study was conducted to ascertain the range of induced hemolyzed blood/serum delta 9-tetrahydrocannabinol (delta 9-THC) concentrations in 58 human subjects. Subjects were tested within 5 min of smoking a delta 9-THC cigarette and then at half-hour intervals to 150 min. The subjects initially demonstrated a broad range of delta 9-THC hemolyzed blood levels, which settled within an hour to levels comparable to those measured in California drivers who had been stopped for impaired driving, arrested, and tested for delta 9-THC. Serum levels, when correlated with performance or roadside sobriety tests, demonstrated a broad range (5 to 183 ng/mL) of delta 9-THC levels and an "adaptation" effect in the subjects' perception of their own impairment. Although this preliminary study was not a double-blind placebo experiment, the overall performance of human subjects demonstrated the "adaptation" effect, which may be a significant factor in making judgments while performing such complex tasks as driving. Also, the effects of the drug extended beyond the period of elevated delta 9-THC blood levels, perhaps because of THC metabolites that may contribute to impairment or the persistence of THC in the central nervous system. This pilot study will lay the groundwork for a program designed to determine the epidemiology and behavior correlates of marijuana use in motorists.

Ultrastructure of uteroplacental arteries.

Ultrastructural study of the placental bed spiral arteries confirms that non-villous cytotrophoblast is involved in the development of the physiological changes occurring in these vessels during normal pregnancy. The changes observed in the myometrial segments of the spiral arteries before the time of arrival of endovascular trophoblast but after the invasion of the myometrium by migrating interstitial trophoblast, are characterised by widening of the lumen, oedema of the intima, disruption of the elastica and widening of the intercellular spaces of the media. This vascular distension could facilitate the subsequent retrograde migration of endovascular trophoblast. The fetal cells migrate in the vessel lumen and infiltrate the subendothelial space causing further disruption of the arterial intima and media. The altered intima is subsequently recovered by the endothelium. In this way, the cytotrophoblast is incorporated into the wall of the placental bed spiral arteries which are converted from small muscular arteries into distended hyalinized tubes. In pregnancies complicated by preeclampsia and in some pregnancies complicated by fetal growth retardation, these physiological changes are largely restricted to the decidual segments leaving the myometrial segments unaffected. The lesion of acute atherosis is characterised by thickening of the intima and necrosis of the media. The intimal thickening is due to deposition of fibrin and other plasma constituents and migration into the intima of macrophages and myointimal cells which accumulate fat in their cytoplasm to become foam cells. Clinical and experimental studies indicate that these lesions can be initiated by several factors which cause endothelial injury.