Understanding the mechanisms underlying cognitive control in psychosis.

BACKGROUND: Cognitive control (CC) involves a top-down mechanism to flexibly respond to complex stimuli and is impaired in schizophrenia. METHODS: This study investigated the impact of increasing complexity of CC processing in 140 subjects with psychosis and 39 healthy adults, with assessments of behavioral performance, neural regions of interest and symptom severity. RESULTS: The lowest level of CC (Stroop task) was impaired in all patients; the intermediate level of CC (Faces task) with explicit emotional information was most impaired in patients with first episode psychosis. Patients showed activation of distinct neural CC and reward networks, but iterative learning based on the higher-order of CC during the trust game, was most impaired in chronic schizophrenia. Subjects with first episode psychosis, and patients with lower symptom load, demonstrate flexibility of the CC network to facilitate learning, which appeared compromised in the more chronic stages of schizophrenia. CONCLUSION: These data suggest optimal windows for opportunities to introduce therapeutic interventions to improve CC.

Telomere length is a novel predictive biomarker of sensitivity to anti-EGFR therapy in metastatic colorectal cancer.

BACKGROUND: Telomeres are TTAGGG tandem repeats capping chromosomal ends and partially controlled by the telomerase enzyme. The EGFR pathway putatively regulates telomerase function, prompting an investigation of telomere length (TL) and its association with anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer (mCRC). METHODS: Colorectal cancer cell lines were treated with multiple drugs and sensitivity determined. Clinical information was gathered from 75 patients who had received anti-EGFR drugs. Telomere length was measured using a validated qRT-PCR technique. RESULTS: In CRC cell lines, TL independently predicted cetuximab sensitivity. Cells with shorter TL had growth inhibition of 18.6±3.41% as compared with 41.39±8.58% in longer TL (P=0.02). These in vitro findings were validated clinically, in a robust multivariate model. Among patients with KRas WT tumours, those with longer TL had a superior median progression-free survival (PFS) of 24.9 weeks than those with shorter TL; median 11.1 weeks, HR 0.31; P=0.048. CONCLUSION: Telomere length could be a potential unique biomarker predictive of clinical benefit (PFS) of mCRC patients treated with anti-EGFR therapy. This is the novel demonstration of a complex hitherto undescribed interaction, placing anti-EGFR therapy, EGFR pathway, and the telomerase complex within a clinical context.

ZNF804A genetic variation (rs1344706) affects brain grey but not white matter in schizophrenia and healthy subjects.

BACKGROUND: Genetic variation in the gene encoding ZNF804A, a risk gene for schizophrenia, has been shown to affect brain functional endophenotypes of the disorder, while studies of white matter structure have been inconclusive. METHOD: We analysed effects of ZNF804A single nucleotide polymorphism rs1344706 on grey and white matter using voxel-based morphometry (VBM) in high-resolution T1-weighted magnetic resonance imaging scans of 62 schizophrenia patients and 54 matched healthy controls. RESULTS: We found a significant (p < 0.05, family-wise error corrected for multiple comparisons) interaction effect of diagnostic group x genotype for local grey matter in the left orbitofrontal and right and left lateral temporal cortices, where patients and controls showed diverging effects of genotype. Analysing the groups separately (at p < 0.001, uncorrected), variation in rs1344706 showed effects on brain structure within the schizophrenia patients in several areas including the left and right inferior temporal, right supramarginal/superior temporal, right and left inferior frontal, left frontopolar, right and left dorsolateral/ventrolateral prefrontal cortices, and the right thalamus, as well as effects within the healthy controls in left lateral temporal, right anterior insula and left orbitofrontal cortical areas. We did not find effects of genotype of regional white matter in either of the two cohorts. CONCLUSIONS: Our findings demonstrate effects of ZNF804A genetic variation on brain structure, with diverging regional effects in schizophrenia patients and healthy controls in frontal and temporal brain areas. These effects, however, might be dependent on the impact of other (genetic or non-genetic) disease factors.

Blockage of NF-kappa B signaling by selective ablation of an mRNA target by 2-5A antisense chimeras.

Activation of 2-5A-dependent ribonuclease by 5'-phosphorylated, 2',5'-linked oligoadenylates, known as 2-5A, is one pathway of interferon action. Unaided uptake into HeLa cells of 2-5A linked to an antisense oligonucleotide resulted in the selective ablation of messenger RNA for the double-stranded RNA (dsRNA)-dependent protein kinase PKR. Similarly, purified, recombinant human 2-5A-dependent ribonuclease was induced to selectively cleave PKR messenger RNA. Cells depleted of PKR activity were unresponsive to activation of nuclear factor-kappa B (NF-kappa B) by the dsRNA poly(I):poly(C), which provides direct evidence that PKR is a transducer for the dsRNA signaling of NF-kappa B.

Selective modulation of collagenase 1 gene expression by the chemotherapeutic agent doxorubicin.

Matrix metalloproteinases (MMPs) play a crucial role in tumor cell invasion and metastasis due to their ability to digest basement membrane and extracellular matrix components, thereby facilitating cell movement through connective tissues. At noncytotoxic concentrations, i.e., concentrations lower than those normally used in cancer chemotherapy, the anthracycline doxorubicin specifically inhibited collagenase 1 (MMP-1) gene expression in the highly invasive and metastatic human melanoma cell line A2058. This inhibition was specific for collagenase 1 because it did not affect the expression of two other MMPs, gelatinase A (MMP-2) and gelatinase B (MMP-9). The reduction in collagenase 1 expression correlated with a decrease in the invasive ability of tumor cells through a collagen type I matrix and was independent of the cytotoxic and antiproliferative effects usually associated with this anticancer drug. The selective modulation of collagenase 1 expression by nontoxic doses of doxorubicin suggests a novel application for this chemotherapeutic agent, perhaps in combination therapy, because it decreases the invasive/metastatic potential of melanoma cells that are otherwise unaffected by this drug.

Correlation of selective modifications to a 2',5'-oligoadenylate-3',5'-deoxyribonucleotide antisense chimera with affinity for the target nucleic acid and with ability to activate RNase L.

The use of an antisense oligonucleotide to address a specific targeted RNA sequence and subsequent localized activation of the 2-5A-dependent RNase (RNase L) to effect selective RNA degradation is a new approach to the control of gene expression called 2-5A-antisense. The previously reported biological activity of the 2-5A:AS chimeric oligonucleotide [p5'(A2'p)3A-antiPKR1], directed against nucleotides 55-73 of the coding sequence of the PKR mRNA, has been used as a point of reference to examine the effect of introducing mismatches into the chimeric oligonucleotide, altering the chain length of the antisense domain of the chimeras, removal of the 5'-monophosphate moiety, shortening the 2',5'-oligoadenylate domain, and substitution of 3',5'-linked 2'-deoxyadenosine nucleotides for the 2-5A domain. The general formula for the novel chimeric oligonucleotides is p5'(A2'p)3A2'p(CH2)4p(CH2)4p(5'N3'p)mN, where N is any nucleoside and m is any integer. When the biological activity of these new chimeric oligonucleotides was compared to that of the parent chimera, 2-5A-aPKR, for their ability to effect target PKR RNA cleavage in a cell-free and in an intact cell assay, it was determined that there was a close correlation between the activity of 2-5A-antisense chimeras and their affinity (Tm) for a targeted nucleic acid. In addition, there was also a close correlation between activity of the 2-5A-antisense chimeras and their ability to activate the 2-5A-dependent RNase L.

Nuclease-resistant composite 2',5'-oligoadenylate-3', 5'-oligonucleotides for the targeted destruction of RNA: 2-5A-iso-antisense.

A new modification of 2-5A-antisense, 2-5A-iso-antisense, has been developed based on a reversal of the direction of the polarity of the antisense domain of a 2-5A-antisense composite nucleic acid. This modification was able to anneal with its target RNA as well as the parental 2-5A-antisense chimera. The 2-5A-iso-antisense oligonucleotide displayed enhanced resistance to degradation by 3'-exonuclease enzyme activity such as that represented by snake venom phosphodiesterase and by that found in human serum. 2-5A-Iso-antisense was able to effect the degradation of a synthetic nontargeted substrate, [5'-32P]pC11U2C7, and two targeted RNAs, PKR and BCR mRNAs, in a cell-free system containing purified recombinant human 2-5A-dependent RNase L. These results demonstrated that the novel structural modification represented by 2-5A-iso-antisense provided a stabilized biologically active formulation of the 2-5A-antisense strategy.

Significance of plasma adenosine in the antiplatelet activity of forskolin: potentiation by dipyridamole and dilazep.

Forskolin, a plant (Coleus forskohlii) diterpene, inhibits ADP-induced (human: IC50, 2.3 +/- 1.0 microM; rat: IC50, 1.2 +/- 0.5 microM) and collagen-induced (human: IC50, 2.4 +/- 1.2 microM; rat: 0.6 +/- 0.2 microM) platelet aggregation in human and rat platelet-rich plasma (PRP). Human blood levels of adenosine (Ado) are low (100-300 nM) as compared to levels in rat plasma (7.55 +/- 0.51 microM). Ado is a natural antiplatelet and vasodilatory agent produced by vascular endothelium, heart and other body tissues. If the plasma Ado is degraded by pretreatment of PRP with adenosine deaminase (ADA), forskolin inhibition on platelet aggregation is reduced by 2-4 fold both in human and rat blood. On the other hand, if the physiological steady state levels of Ado are maintained by collecting the blood in the presence of the inhibitors of ADA (2'-deoxycoformycin, dCF, 5 microM) and Ado uptake (dipyridamole, 10 microM or dilazep, 2 microM), forskolin inhibition (IC50, 3.2 microM) on platelet aggregation in human PRP is potentiated by 20-40 fold (IC50, 0.075-0.15 microM). Similar potentiated forskolin effect (IC50, 0.53 microM) is seen if the ADA-treated human PRP is replenished with a low level of Ado (50 nM) after ADA inactivation by dCF and Ado-uptake blockade by dilazep. If the plasma is replenished with a higher concentration of Ado (300 nM), greater potentiation is seen (IC50, 0.23 microM). Forskolin is 2-4 fold more inhibitory in rat PRP than in human PRP, partially due to the presence of higher levels of Ado in the rat plasma. These studies demonstrate an important role of plasma Ado in the antiplatelet activity of forskolin and this effect can be greatly potentiated by the clinically used drugs, dipyridamole and dilazep.

The nef gene from a long-term HIV type 1 nonprogressor.

We examined the nef gene of HIV-1 in a long-term nonprogressor to look for evidence suggesting an attenuated virus. The nef gene was previously shown to be required for induction of AIDS. Simian immunodeficiency virus (SIV) deleted in nef, while infectious, fails to sustain the high viral loads necessary for the induction of AIDS in infected adult rhesus monkeys. The human subject of this report was found to harbor virus (HIV-1 Sur25) encoding open-nef reading frames. However, the nef genes of this subject bore a signature point mutation: a cysteine at amino acid 138. The sequence at this position was identical in all clones examined over a 3-year period. When this sequence was compared to the sequence database for AIDS and human retroviruses at Los Alamos, New Mexico, several isolates from other asymptomatic individuals were also found to encode nef genes with a cysteine at position 138. Furthermore, Cys-138 was found in chimpanzee immunodeficiency virus (CIV), a lentivirus that is similar to HIV but does not cause AIDS in chimpanzees. Multiple cysteines are also found in the nef gene of African green monkey virus, SVIagm, including cysteine at the position analogous to Cys-138. While seroprevalence of SIVagm is high in the wild, there is no known disease associated with this virus. The pathogenic virus isolated from Asian macaques, SIVmac, encodes a Nef protein that has few cysteines. Although the virus HIVSur25 encodes a completely open-nef gene, the virus from this individual is similar to attenuated SIVmac (SIVmac239/nef-deletion) as well as HIV deleted in nef in its growth properties in H9 cells. Nef containing a cysteine at position 138 was shown to be responsible for determining the ability to grow in H9.

Gastric secretion during aging in pyloric-ligated rats and effects of pentagastrin.

Changes in basal- and pentagastrin-stimulated gastric acid, pepsin secretion as well as gastric mucosal histidine decarboxylase activity were examined in 4- to 21-month-old pyloric ligated Fischer-344 rats. In addition, serum gastrin levels, gastric mucosal DNA, and RNA content were determined in these rats. The results revealed that whereas acid secretion decreased progressively with age, pepsin output increased between 4 and 14 months of age and then decreased sharply. Serum gastrin levels decreased progressively with age, and 3 h of pyloric obstruction produced no apparent change in serum gastrin levels in any of the age groups. Gastric mucosal weight, DNA, and RNA content in 4-month-old rats were not significantly different from those of 14-month-old animals. However, in 21-month-old rats, each of these values were found to be significantly lower than in their 4- or 14-month-old counterparts. A single injection of pentagastrin (250 micrograms/kg) significantly stimulated acid and pepsin secretion (45-52%) in 4-month-old rats, but not in 14- and 21-month-old animals, when compared with the corresponding saline-injected controls. Gastric mucosal histidine decarboxylase activity increased steadily between 4 and 21 months of age. Pentagastrin caused a significant 78% stimulation in histidine decarboxylase activity in 4-month-old rats, but had no effect on the enzyme activity in 14-month-old animals, when compared with the corresponding saline-injected controls. However, in 21-month-old rats, pentagastrin inhibited histidine decarboxylase activity by 55% when compared with the saline-injected controls. It is concluded that a) aging decreases capacity of the gastric mucosa to secrete acid and pepsin, b) in aged rats, decreased acid and pepsin output could in part be attributed to mucosal atrophy; c) responsiveness of the gastric mucosa to pentagastrin decreases with age; and d) in aged animals, gastric acid secretion is not regulated by histamine.

Subunit dependent modulation of GABAA receptor function by neuroactive steroids.

Neurosteroids are potent, endogenous modulators of GABAA receptor function in the central nervous system. The endogenous progesterone metabolite allopregnanolone (ALP) and the synthetic steroid compound alphaxalone (AFX) have been shown to both directly activate and potentiate GABAA receptor-activated membrane current (IGABA). The role of different alpha and gamma subunit subtypes in modulation of IGABA by ALP and AFX was investigated using recombinant GABAA receptor isoforms expressed in Xenopus oocytes. Changing or removal of the alpha subunit subtype altered the efficacy of both ALP and AFX (alpha2beta1gamma2L>alpha1beta1gamma2L>>beta1gamma2L) to potentiate IGABA, but did not alter the potency of the neuroactive steroids at these receptor isoforms. The efficacy of ALP to enhance IGABA was also dependent on the gamma subunit subtype (alpha1beta1gamma3>alpha1beta1gamma2L = alpha1beta1gamma1). AFX also had higher efficacy in the alpha1beta1gamma3 receptor isoform compared to alpha1beta1gamma1. In contrast to ALP, the potency of AFX was greater in the alpha1beta1gamma3 and alpha1beta1gamma1 receptor isoforms compared to alpha1beta1gamma2L. This study provides evidence that the alpha subunit subtype determines the efficacy, but not the potency, of these neuroactive steroids to potentiate IGABA. The gamma3 subunit subtype increases the maximal efficacy of neuroactive steroids compared to other gamma subunit subtypes. These results suggest that the heteromeric assembly of different GABAA receptor isoforms containing different subunit subtypes results in multiple steroid recognition sites on GABAA receptors that in turn produce distinctly different modulatory interactions between neuroactive steroids acting at the GABAA receptor.

Propofol and flurazepam act synergistically to potentiate GABAA receptor activation in human recombinant receptors.

The intravenous general anaesthetic propofol (2,6-di-isopropylphenol) is frequently combined with a benzodiazepine. There are clinical reports of synergism between these two agents for induction of general anaesthesia. To investigate a possible mechanism of this synergistic interaction between propofol and benzodiazepines, the effect of propofol and flurazepam on GABAA receptor function was examined in Xenopus oocytes expressing recombinant alpha 1 beta 2 gamma 2L and alpha 2 beta 2 gamma 2L receptor constructs. Potentiation of GABA receptor-activated current by low (1-10 microM) concentrations of propofol together with flurazepam (0.25-0.5 microM) was significantly greater than predicted by an additive response. Isobolographic analysis indicated a strong synergistic interaction between propofol and flurazepam at either of the receptor constructs examined. In contrast, the cyclopyrrolone derivative zopiclone, which produced a similar facilitation of GABA receptor-activated current compared to flurazepam, produced a less than additive potentiation when combined with propofol. Flurazepam significantly decreased the EC50 concentration of propofol for potentiation of GABA responses. Thus, flurazepam, in addition to facilitating GABA receptor activity on its own, also increases on its own, also increases the apparent affinity of the GABAA receptor complex to propofol, resulting in a greater than expected potentiation by the combination of propofol plus flurazepam.

Targeting RNase L to human immunodeficiency virus RNA with 2-5A-antisense.

In an attempt to develop a lead for the application of 2-5A-antisense to the targeted destruction of human immunodeficiency virus (HIV) RNA, specific target sequences within the HIV mRNAs were identified by analysis of the theoretical secondary structure. 2-5A-antisense chimeras were chosen against a total of 11 different sequences: three in the gag mRNA, three in the rev mRNA and five in the tat mRNA. 2-5A-antisense chimera synthesis was accomplished using solid-phase phosphoramidite chemistry. These chimeras were evaluated for their activity in a cell-free assay system using purified recombinant human RNase L to effect cleavage of 32P-labelled RNA transcripts of plasmids derived from HIV NL4-3. This screening revealed that of the three 2-5A-antisense chimeras targeted against gag mRNA, only one had significant HIV RNA cleavage activity, approximately 10-fold-reduced compared to the parent 2-5A tetramer and comparable to that reported for the prototypical 2-5A-anti-PKR chimera, targeted against PKR mRNA. The cleavage activity of this chimera was specific, since a scrambled antisense domain chimera and a chimera without the key 5'-monophosphate moiety were both inactive. The 10 other 2-5A-antisense chimeras against tat and rev had significantly less activity. These results imply that HIV gag RNA, like PKR RNA and a model HIV tat-oligoA-vif RNA, can be cleaved using the 2-5A-antisense approach. The results further imply that not all regions of a potential RNA target are accessible to the 2-5A-antisense approach.

An approximate bootstrap technique for variance estimation in parametric images.

Parametric imaging procedures offer the possibility of comprehensive assessment of tissue metabolic activity. Estimating variances of these images is important for the development of inference tools in a diagnostic setting. However, these are not readily obtained because the complexity of the radio-tracer models used in the generation of a parametric image makes analytic variance expressions intractable. On the other hand, a natural extension of the usual bootstrap resampling approach is infeasible because of the expanded computational effort. This paper suggests a computationally practical, approximate simulation strategy to variance estimation. Results of experiments done to evaluate the approach in a simplified model one-dimensional problem are very encouraging. Diagnostic checks performed on a single real-life positron emission tomography (PET) image to test for the feasibility of applying the procedure in a real-world PET setting also show some promise. The suggested methodology is evaluated here in the context of parametric images extracted by mixture analysis; however, the approach is general enough to extend to other parametric imaging methods.

Restoration of pedicle screw fixation with an in situ setting calcium phosphate cement.

STUDY DESIGN: Pedicle screws were pulled out of human cadaveric vertebrae before and after augmentation with polymethylmethacrylate or in situ-setting calcium phosphate cement. The fixation strength of screws augmented with calcium phosphate cement was compared with that of screws augmented with polymethylmethacrylate. OBJECTIVES: To determine whether a new in situ-setting calcium phosphate cement might be suitable for augmenting the fixation of pedicle screws. The principle objective was to compare the pull-out resistance of screws augmented with calcium phosphate cement with the pull-out behavior of screws augmented with polymethylmethacrylate. Polymethylmethacrylate augmentation was chosen as the standard because of its current clinical use. Five types of screws were tested to determine whether screw design had an effect on the efficacy of augmentation. SUMMARY OF BACKGROUND DATA: Although many factors affect the pull-out resistance of pedicle screws, a key determinant of their performance is the strength of their attachment to the spine. In elderly, osteopenic patients, the screw-bone interface is especially at risk for stripping during insertion or pull-out after surgery. In these patients, polymethylmethacrylate has been used to augment pedicle screw fixation, although its use is not without risk. In situ-setting calcium phosphate cements may provide an alternative to polymethylmethacrylate in this application. Like polymethylmethacrylate, calcium phosphate cements can be injected into the prepared screw hole. They have the added advantage of being resorbed and replaced during healing and normal bone remodeling. METHODS: Thirty human lower lumbar vertebrae (L3-L5) were implanted bilaterally with one of five types of pedicle screws (n = 6 for each screw type). The screws were pulled out 3.0 mm at 0.25 mm/sec with a servohydraulic materials testing machine. The 3.0-mm pull-out distance, which was slightly longer than one thread pitch, was designed to strip the screw-bone interface but to leave the pedicle otherwise intact. After the initial testing, the screws in each vertebrae were removed, and the screw tracks were filled with 2.0 cc of polymethylmethacrylate (one side) or calcium phosphate cement (contralateral side). After augmentation, the screws were reinserted, and the cements were allowed to harden for 24 hours. Postaugmentation testing followed the protocols for preaugmentation testing, and the pull-out resistance of screws augmented with calcium phosphate cement was compared with the pull-out resistance of screws augmented with polymethylmethacrylate. RESULTS: Mechanically, calcium phosphate cement compared favorably with polymethylmethacrylate for augmenting pedicle screws. Both restored the strength of the screw-bone interface: across all screw types, the average increase in pull-out strength was 147% with polymethylmethacrylate augmentation and 102% with calcium phosphate cement. There were no significant differences because of screw type with either type of augmentation. CONCLUSIONS: The in situ-setting calcium phosphate cement investigated in this study compared favorably with polymethylmethacrylate in a single-cycle, pull-out test of augmented pedicle screws in senile trabecular bone. With further evaluation, this cement may offer an alternative to polymethylmethacrylate for the enhancement of pedicle screw fixation clinically.

Intramedullary ancient schwannoma of the cervical spinal cord: case report and review of literature.

We report a rare case of intramedullary ancient schwannoma of cervical spinal cord in a 68 year old patient. About 49 cases of intramedullary schwannomas and neurofibromas have been reported in the literature but to our knowledge there is no report of the 'ancient' variety of intramedullary schwannoma. The cell of origin of these tumours is the schwann cell, which normally does not exist in the parenchyma of the central nervous system. Many theories have been advanced to explain this paradox. According to one theory, these tumours arise from the perivascular nerve plexus of the pial vessels. This plexus was found mostly to exist along the branches of the anterior spinal artery. In our case, the tumour was supplied by two branches of the anterior spinal artery, which may add further support to the above theory.

Stress fractures. Clinical history and physical examination.

The incidence of stress fractures is increasing among competitive and recreational athletes as well as among children and the elderly. By understanding the continuum of bone's response to stress and maintaining an appropriate index of suspicion, the health care provider can diagnose these injuries appropriately. An accurate history and examination is essential and will differentiate stress fractures from other stress reactions. The more common stress fractures are discussed.

Isolated dislocation of the middle cuneiform in a farmer: a case report and review of the literature.

Isolated dislocations of the middle cuneiform are uncommon. There have been four reported previously. Significant force is required to produce these injuries, and they can have serious neurovascular consequences. In this case report and review of the literature, we present an isolated middle cuneiform dislocation in a 69-year-old farmer with impending skin and soft tissue loss over the dislocated bone.

Meniscal reconstruction. Part II: Outcome, potential complications, and future directions.

Currently, magnetic resonance imaging and second-look arthroscopy are the only methods available to objectively evaluate the outcome of meniscal reconstruction. While clinical studies indicate progressively improving outcomes of meniscal reconstruction, longer follow-up is needed to determine whether the natural history of joint degeneration can be altered. Part I of this comprehensive review, published in the April 1999 issue, discussed the anatomy and function of the meniscus, followed by the indications, techniques, and graft considerations for meniscal allograft reconstruction. Part II reviews the results, potential complications, and future directions of meniscal allograft reconstruction.

Meniscal reconstruction. Part I: indications, techniques, and graft considerations.

Menisci are specialized structures capable of bearing loads, absorbing shock, stabilizing, and lubricating the knee joint. Increased knowledge of meniscal anatomy and function, as well as studies of chronic anterior cruciate ligament-deficient and -reconstructed knees, have indicated that loss of meniscal function is associated with progression of degenerative changes within the knee. Meniscal reconstruction has been developed to preserve those functions prior to the development of significant degenerative changes in patients who have undergone meniscectomy. Indications are still being defined. Meniscal reconstruction has been achieved by either arthroscopically assisted or open techniques. Anatomic placement and secure fixation of the graft are requirements to allow the optimal revascularization needed for successful incorporation of the graft. Part I of this review will discuss the anatomy and function of the meniscus, followed by the indications, techniques, and graft considerations for meniscal allograft reconstruction. In Part II, which will be published in the May 1999 issue, we will review the results, potential complications, and future directions of meniscal allograft reconstruction.