Lung cancer is now considered the most common cause of death among cancer patients. Although target biological regimens have emerged in recent years for non-small cell lung carcinoma, the survival and quality of life of patients with this condition still remain low. The five-year survival rate for all stages of lung cancer is 17% or less.2M0) non-small cell lung carcinoma (adenocarcinoma) and underwent a complete left upper lobectomy three years ago. After two and a half years of follow-up, she suddenly presented with facial edema and venous distension and was immediately treated for superior vena cava syndrome. Because of a diagnostic check, a major clot was detected in the right subclavian vein. Our patient was informed about treatment options, and she was taken to the catheterization laboratory for percutaneous stenting of the superior vena cava to restore superior vena cava patency.We describe the case of a 53-year-old Caucasian woman who was diagnosed with advanced stage IIIa (T2aNLung cancer has a vast number of complications. Superior vena cava syndrome and thrombosis should be considered upon the presentation of a patient with obstructive symptoms. In this case report, even though we expected the clot to be on the side of the former lesion, it was present on the opposite side. Treatment should also start immediately in these patients with clinical suspicion of thrombosis to avoid further complications, even in cases with a differential diagnosis problem. Finally, although patients with non-small cell lung carcinoma have a high incidence of thromboembolic events, anticoagulant treatment is given only as maintenance therapy after a first event occurs. Lung cancer is one of the leading causes of death in the European Union, with an incidence of approximately 180,000 cases per year  in appro2M0-IIIa). It was first diagnosed three years before as a left upper lobe mass attached to the mediastinum and was treated with left upper lobe complete resection. The pathologic examination revealed poorly differentiated adenocarcinoma. Our patient was subsequently treated with six cycles of taxane and platinum chemotherapy and radiotherapy at the primary site. It was decided to initiate a complete chemotherapy regimen for locally advanced lymph node disease N2. After two and a half years of follow-up, our patient was diagnosed with progressive disease (left supraclavicular nodes and sternum bone metastases), and at the time of examination, she was not receiving any treatment. Her physical examination revealed facial edema and thoracic and upper limb venous distension  141.4 mEq/L, potassium (K+) 4.3 mEq/L, calcium (Ca2+) 8.9 mg/dL, uric acid 4.1 mg/dL, international normalized ratio (INR) 0.94, and D-dimers 4300 μg/mL.A 53-year-old Caucasian woman consulted our department complaining of progressively worsening facial swelling and a feeling of "tension in the head," which she had first experienced eight days previously and had gradually worsened. Our patient had a history of locally advanced lung cancer  was performed to confirm the diagnosis. Enhanced neck CT demonstrated a major thrombus-like lesion inside her right jugular vein Figure . The staet al. [Malignancy in non-small cell lung carcinoma (NSCLC) is the most common cause of SVCS, as a result of either compression of the SVC by an adjacent tumor or compression by mediastinal lymph nodes. However, because the velocity of blood flow in the SVC is too fast to permit blood thrombosis, the development of SVC thrombosis alone is extremely rare -6. In paSVCS is often diagnosed clinically on the basis of symptoms of venous congestion, including facial and neck swelling, dyspnea and headache. Venous Doppler ultrasonography, contrast-enhanced CT and magnetic resonance imaging are contributory diagnostic modalities when the diagnosis is unclear . In maliEndovascular options for the treatment of patients with SVCS in the setting of lung cancer include thrombolysis, angioplasty and stent placement. The use of angioplasty and stenting has developed over the past 15 years. Initially, SVC stents were used in patients who failed to respond to traditional therapy or whose symptoms recurred after traditional therapy. In this patient population, SVC stents have had dramatic technical and clinical results; relief of SVC obstruction has been demonstrated in more than 90% of these patients and obtained with a delay of 24 to 72 hours . With thComplications of stent placement have been reported in 3% to 7% of patients with SVCS . The mosCancer patients undergoing surgery or bedridden with acute medical illness should receive routine thromboprophylaxis . In cancer patients with indwelling central venous catheters, the American College of Chest Physicians (ACCP) advises against using prophylactic doses of low-molecular-weight heparin or mini-dose warfarin  for the prevention of catheter-related thrombosis. The routine use of thromboprophylaxis for primary prevention of venous thromboembolic event (VTE) is not recommended for cancer patients receiving chemotherapy or hormonal therapy. The routine use of primary thromboprophylaxis for improvement of survival in cancer patients is also not recommended .In our report, we present the case of a patient with upper left lobe lung disease and cancer-related thrombosis of the right subclavicular vein that led to SVCS after surgical resection. We report this case because we would usually expect the thrombus to form on the left hemithorax because of the regional effects of the cancer cells. Also, at the time of symptom presentation, our patient did not have lung disease. This case report illustrates the effectiveness of vascular stenting in the management of SVCS in a lung cancer patient with subclavicular thrombosis. Because SVC obstruction is a highly stressful complication for patients with lung cancer, we used endovascular stenting as the main therapeutic intervention for an effective and fast-acting procedure. Our patient was in addition receiving anticoagulation therapy for the prevention of further thrombosis and recurrence. We believe that, given the efficacy of endovascular stenting, future patients will undergo vascular stenting as the first-line treatment despite the elevated cost of this relatively new technique.Lung cancer is a well-known predisposing factor for thrombosis. Central venous thrombosis should be included in the differential diagnosis of a patient with symptoms that could be attributed to venous obstruction. The results achieved with endovascular stents in the treatment of SVCS of malignant causes are excellent, and percutaneous endovascular stent insertion is an effective treatment for palliation of SVCS because it provides immediate and sustained symptomatic relief. The high response rates, quickness of effect and safety make this palliative treatment a useful tool and a candidate for being the potential standard in the management of SVC obstruction. It has not yet been established whether cancer patients without locally recurrent disease should receive anticoagulant therapy. The risk of deep venous thrombosis is low in cancer patients without additional risk factors. This fact is in accordance with the ACCP guidelines, which do not recommend routine prophylaxis for VTE prevention in cancer patients in itself . The risWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.PZ was responsible for the medical care of the patient and was a contributor in writing the manuscript. ET was a major contributor in writing the manuscript. GK was also responsible for the patient's medical care. VZ was the vascular surgeon responsible for placing the stent. TK diagnosed the patient on the basis of bronchoscopy. AM was the surgeon who performed the lobotomy. KZ is the head of the department and responsible for the patient's medical care. All authors read and approved the final manuscript.


Upper gastrointestinal bleeding due to duodenal metastases is extremely uncommon. Extra-pelvic spread of squamous cell carcinoma (SCC) of the cervix to the small bowel is rare with only 6 reported cases in the English literature since 1981.We report the case of a 49-year-old woman who presented with upper-gastrointestinal bleeding two years after the diagnosis of SCC of the cervix. At esophagogastroduodenoscopy, there was a stricture in the second part of the duodenum which was biopsied for a suspected neoplastic lesion. Histologic and immunohistochemical examination showed a malignant lesion with characteristics identical to her original tumor in the cervix confirming the duodenal metastases.The clinical presentation of a 'malignant' upper-gastrointestinal bleed due to duodenal metastases from SCC of the cervix is unusual. Awareness of such infrequent patterns of metastases in cervical cancer confirmed by histopathological diagnosis is important for best practice therapeutic decisions in these patients. Histopathology specimens of small bowel lesions are infrequently encountered in surgical pathology. Malignant diagnosis of such lesions accounts for only 0.4% of all cancers and 0.2% of cancer-related deaths . MetastaWe herein report a case of duodenal metastases from SCC of the cervix confirmed by histopathological diagnosis that presented with upper gastrointestinal bleeding. In addition, we have provided a comprehensive review of all reported cases of SCC of the cervix metastasizing to the small bowel in the published English literature by a PubMed and Medline search as available since 1981.*) as seen in Figures A 49 year-old female presented as a surgical emergency with massive upper gastrointestinal (GI) bleeding. Her significant past history included chemotherapy and radiation treatment for invasive squamous cell carcinoma (stage IIa) of the cervix with extension to the urinary bladder two years ago. Her upper GI bleed was investigated with an emergency esophagogastroduodenoscopy. The stomach, fundus, and GI junction all appeared completely normal; however, it was difficult to advance the scope beyond the second part of the duodenum due to a stricturing abnormality. This abnormal area was suspected for an underlying neoplastic process and a tissue biopsy was obtained. While awaiting pathological confirmation of the exact nature of this neoplastic lesion, the patient was investigated with computed tomography (CT) scans as part of pre-surgical workup. The CT scans confirmed the presence of large soft-tissue mass completely encircling the abdominal aorta (▲) and impinging on the adjacent duodenum  of the cervix is the second most common gynecologic malignancy ,10. In tCarcinoma of the cervix usually spreads in an orderly and predictable fashion . The earNeoplasms in the small bowel are rare, with a global incidence of less than 1.0 per 100 000 people . MetastaIt remains puzzling why small-bowel metastases are such rare events, even though anatomically the small intestine makes up 75% of the length and 90% of the absorptive surface of the esophagogastrointestinal system ,13. SeveUnlike the solid feces passing through the colon, chyme of the small intestine is liquefied, causing less mucosal irritation and reducing mechanical trauma. Additionally, transit through the small intestine is more rapid than through the large intestine, thereby shortening the exposure of potential carcinogens in the chyme to the mucosal surface.Immune protection is abundant through the small intestine, with numerous lymphoid cells in the mucosa and submucosa. Further, the small bowel is responsible for large secretions of IgA, an antibody intimately involved in mucosal protection. Compared to the rest of the population, patients on immunosuppressive agents have an increased risk of tumorigenesis in the small bowel. Additionally, immunological abnormalities such as IgA deficiency, Crohn's and celiac disease have a greater propensity for the development of small bowel tumors.As the bacterial counts in the small bowel are absent or considerably lower than the large bowel, there is minimal exposure to the potentially carcinogenic chemical products of bacterial breakdown. Additionally, the relative intraluminal alkalinity of the small bowel can prevent the formation of potentially carcinogenic nitrosamines. Furthermore, the small bowel contains benzopyrene hydroxylase and other tumor-inhibiting components that may aid in neutralizing carcinogens.It is estimated that every sixteen minutes, one gram of small intestinal mucosa is replaced, and the entire mucosal layer including the absorptive, glandular, and neuroendocrine cells is restored every 4-7 days. Such high turnaround of mucosal cells is probably incompatible with the "critical cell mass" required for tumorigenesis. Liquefied chyme in the small bowel may act as a mucosal barrier to potential carcinogens. Additionally, small bowel stem cells are well protected as they are buried deep within the crypts.A detailed review of the published English literature yielded only six cases of squamous cell carcinoma of the cervix with documented metastases to the small bowel Table . The mosIn conclusion, duodenal metastasis from SCC of the cervix is an extremely uncommon 'malignant' cause of upper gastrointestinal bleeding. Yet, accurate recognition of such unusual patterns of metastases in cervical cancer by histopathology is vital for best practice therapeutic decisions in these patients.The authors declare no conflicts of interest.All authors participated fully in the conception, development, and creation of this manuscript. All authors read and approved the final version of the manuscript.


The LEAR structure is a flexible two-parameter correlation model that applies to situations in which the within-subject correlation decreases exponentially in time or space. It allows for an attenuation or acceleration of the exponential decay rate imposed by the commonly used continuous-time AR(1) structure. We propose the Kronecker product LEAR correlation structure for multivariate repeated measures data in which the correlation between measurements for a given subject is induced by two factors . Excellent analytic and numerical properties make the Kronecker product LEAR model a valuable addition to the suite of parsimonious correlation structures for multivariate repeated measures data. Longitudinal medical imaging data of caudate morphology in schizophrenia illustrates the appeal of the Kronecker product LEAR correlation structure.Longitudinal imaging studies have moved to the forefront of medical research due to their ability to characterize spatio-temporal features of biological structures across the lifespan. Credible models of the correlations in longitudinal imaging require two or more pattern components. Valid inference requires enough flexibility of the correlation model to allow reasonable fidelity to the true pattern. On the other hand, the existence of computable estimates demands a parsimonious parameterization of the correlation structure. For many one-dimensional spatial or temporal arrays,  Multivariate repeated measures studies are characterized by data that have more than one set of correlated outcomes or repeated factors. Spatio-temporal data fall into this more general category, since the outcome variables repeat in both space and time. Valid analysis requires accurately modeling the correlation pattern. Muller et al. and Gurka et al. showed that under-specifying the correlation structure can severely inflate test size of tests of fixed effects in the general linear mixed model separable if and only if it can be written as Galecki While separable covariance models are commonly used in the spatial statistics literature Brain morphology research is another area in which separable models would be effective because both the shape of brain structures  and how they change over time  must be analyzed. Our work concerns temporal changes in caudate morphology in schizophrenics. Schizophrenia is characterized by disabling impairments in the perception or expression of reality. Pathological changes in brain morphology in schizophrenics may be progressive and associated with clinical outcome. Much recent work has focused on the effect of antipsychotic drugs on brain morphology consistently-spaced measurements. In the context of spatio-temporal data, this means that at each time point a given subject must have the same number of measurements taken at the same spatial locations.Limitations of separable models have been noted by various authors. Most important, as mentioned in linear exponent autoregressive (LEAR) correlation model, defined in Fitting a Kronecker product structure requires choosing models for each of the factors. In medical imaging, repeated measures dimensions typically have within-subject correlation decreasing exponentially in time or space. The continuous-time, first-order autoregressive correlation structure, denoted AR(1), is often used in longitudinal settings. This model was briefly examined in The advantages of employing a LEAR model for each component led us to consider a Kronecker product LEAR correlation structure for multivariate repeated measures data in which the correlation between measurements for a given subject is induced by two factors. We allow for an imbalance in both dimensions across subjects, i.e., an unequal numbers of observations. The LEAR model also accommodates any arbitrary spacing within a dimension. We use maximum likelihood estimation of the general linear model with Gaussian errors to illustrate the benefits of the structure. All other common estimation methods for linear and nonlinear models could also be used with a Kronecker product LEAR structure.This analysis involved the application of a new method to extant data. The original study was conducted from March 1, 1997 to July 31, 2001 at 14 academic medical centers. All subjects gave written informed consent in accordance with the Declaration of Helsinki. Each site’s institutional review board  approved the study.radius in cm as a measure of local object width at an m-rep node (21 locations per caudate). This measure is represented in Our data came from longitudinal MRI scans of the left caudate for 240 schizophrenia patients and 56 controls. The surface of each object was parameterized via the medial representation (m-rep) method as described in linear exponent autoregressive (LEAR) correlation structures areSuppose The Kronecker product LEAR correlation structure isGraphical depictions of the Kronecker product LEAR structure help to provide insight into the types of correlation patterns that can be modeled. A correlation pattern in which both of the factor-specific matrices  have decay rates slower than that of the AR(1) model is illustrated in Given the advantages of the Kronecker product covariance model, we believe that it has been underutilized in practice. As alluded to in the Introduction, the model has great computational properties and simplifies interpretation. It also reduces the dimension of the calculations, sometimes drastically  estimation of the general linear model where the Gaussian errors have a Kronecker product LEAR correlation structure. We allow for an imbalance in both dimensions of the data. Our moderately large sample context precludes the need for REML estimation.Consider the following general linear model for multivariate repeated measures data with the Kronecker product LEAR correlation structure:Again, Setting The ML estimates of the model parameters may be computed with the Newton-Raphson algorithm, which requires the first and second partial derivatives of the profile log-likelihood. The derivations of the first partial derivatives are available from the authors. The second partial derivatives of the parameters, which are employed to determine the asymptotic variance-correlation matrix of the estimators, may be approximated by finite difference formulas. The derivative approximations are detailed in After getting the estimates of The derivation of this estimator is available from the authors. A SAS IML A possible complication when implementing the Kronecker product LEAR correlation model is that the proposed estimation method can produce negative variance estimates for the correlation parameters. This may occur for the parameters of either one or both of the factor-specific matrices when there is a faster decay rate than that imposed by the AR(1) model coupled with a “small” An alternate approach is to implement an estimation method which only uses first-order derivatives such as a quasi-Newton procedure. An efficient modification of Powell’s We model the caudate data with the general linear model for multivariate repeated measures data defined in the previous section , DE, and LEAR structures in order to assess the best model via the AIC In order to obtain a parsimonious model, the full model defined in There is no evidence of a difference in caudate shape between the treated schizophrenics and the controls when taking into account all images taken over time. To ensure that the Kronecker product LEAR correlation model still provides the better fit for the final model, we again model the temporal and spatial factor-specific correlations of the model errors with the continuous-time AR(1), DE, and LEAR structures. The residual variance estimate and correlation parameter estimates of the Kronecker product LEAR structure (defined in An examination of this approach, and others, will be left for future research.The Kronecker product LEAR correlation model allows modeling and understanding two factor-specific correlation patterns. Excellent analytic and numerical properties make the structure especially attractive for High Dimensional, Low Sample Size settings that are common in longitudinal medical imaging and various kinds of longitudinal “-omics” data. The structure is able to model a wide variety of correlation patterns with just four parameters. Analysis of the caudate data illustrates the interpretability of the model in a complex context.An assessment of model fit and inference accuracy in higher dimensional settings is a priority for future research on Kronecker product LEAR correlation models. Also, introducing a nonstationary Kronecker product LEAR correlation or variance structure may prove extremely useful in neuroimaging, since the variability of brain characteristics tends to vary spatially and temporally. Comparing the implementation of the Kronecker product LEAR structure with various modeling and estimation methods will prove valuable. For data that have within-subject correlations induced by three or more factors, as in longitudinal imaging data represented via the m-rep method (


In view of the growing prevalence of Alzheimer's disease (AD) worldwide, there is an urgent need for the development of better diagnostic tools and more effective therapeutic interventions. At the earliest stages of AD, no significant cognitive or functional impairment is detected by conventional clinical methods. However, new technologies based on structural and functional neuroimaging, and on the biochemical analysis of cerebrospinal fluid (CSF) may reveal correlates of intracerebral pathology in individuals with mild, predementia symptoms. These putative correlates are commonly referred to as AD-related biomarkers. The relevance of the early diagnosis of AD relies on the hypothesis that pharmacological interventions with disease-modifying compounds are likely to produce clinically relevant benefits if started early enough in the continuum towards dementia. Here we review the clinical characteristics of the prodromal and transitional states from normal cognitive ageing to dementia in AD. We further address recent developments in biomarker research to support the early diagnosis and prediction of dementia, and point out the challenges and perspectives for the translation of research data into clinical practice. Alzheimer's disease (AD) is the most common dementing disorder in older people. As a consequence of population aging worldwide, a fourfold increase in the prevalence of AD is expected to occur over the next decades. Recent estimates foresee that more than 80 million individuals will be affected by the disease by 2040, which is a natural consequence of the age-dependent increase in the number of incident cases of AD -3. An imThe National Institute on Aging and the Alzheimer's Association have recently convened working groups to re-edit the diagnostic criteria for AD dementia, taking into account the vast expansion of the knowledge of the neurobiology of the disease, most of which was obviously unavailable by the time the original National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria were launched 26 years ago ,5. AnothIn this review article, we address the clinical characteristics of the prodromal stages of AD and the transitional states from normal cognitive ageing and dementia. We further present recent developments in biomarker research, and the perspectives of using these techniques to reinforce the clinical diagnosis of AD at predementia stages.AD is a chronic neurodegenerative disease with well defined pathological markers, mostly affecting medial temporal lobe and associative neocortical structures. Neuritic plaques and neurofibrillary tangles, the pathological hallmarks of AD, are primarily related to the overproduction and aggregation of the amyloid β peptide (Aβ) within the brain, and to the hyperphosphorylation of Tau protein in affected neurons. These abnormalities lead to the activation of neurotoxic cascades and to cytoskeletal changes that eventually cause neuronal dysfunction and death. Neurofibrillary tangles appear first in allocortical structures, whereas amyloid plaques may first be found in the neocortex . In addiThere is evidence of a long preclinical phase in AD, in which the aforementioned abnormalities gradually accumulate in affected brain areas prior to the presentation of significant cognitive decline and dementia. Recent models based on neuropathological, biochemical and neuroimaging methods have proposed that intracerebral amyloidosis precedes the onset of cognitive symptoms by several years, if not decades. Autopsy studies have shown that intracerebral amyloidosis may be observed in some subjects as early as in the third or fourth decades of life, with increasing magnitude in late middle age, and highest estimates in old age -12. The It is a difficult task to clinically differentiate incipient AD from normal cognitive ageing and from the subtle cognitive changes that arise in other forms of dementia in the prodromal phases. In the early stages, patients with AD may present with mild but persistent (and often progressive) cognitive deficits, albeit not severe enough to warrant the diagnosis of dementia. In the recent literature, individuals in this predementia stage of AD have been most commonly categorized according to the definition of MCI . HoweverDespite this, the long predementia phase in AD constitutes a unique time frame to search for clinical and neurobiological tools to reinforce the cross-sectional diagnosis and to predict the dementia outcome. The neuropathological features of subjects with amnestic MCI are intermediate between those found in cognitively normal and demented individuals Figure . In a clSubtle changes related to the pathological process may be quantified in asymptomatic or mildly symptomatic patients by the assessment of humoral fluids, mostly cerebrospinal fluid (CSF), or by using advanced neuroimaging methods. Therefore, the rationale for the search for biological markers in AD is to increase diagnostic accuracy at early stages of the disease process. The correct use of this information may help identify subjects at risk of developing dementia upon follow-up. However, the clinical benefits will critically depend on the availability of more efficacious therapies to halt cognitive decline and, ideally, to prevent dementia. These include the development of more specific pharmacological interventions targeting the pathological cascades of AD.The cognitive syndrome of early stage AD is primarily represented by encoding and retrieval deficits, resulting in episodic memory impairment and diminished capacity to learn new information -19. Throet al. [The characterization of the cognitive syndrome that best predicts the AD outcome in non-demented patients has been the focus of extensive research in the past decades. However, the clinical picture of predementia AD overlaps with the cognitive changes that occur in normal ageing and other pathological processes. Frequency estimates of cognitive impairment in the older population depend critically on the definition that is adopted to yield the classification of subjects as normal or impaired. However, these different definitions not always agree with respect to the procedures that need to be adopted to rule in and out subtle cognitive deficits. In addition, the output obtained from the classification of individuals according to one given definition of cognitive impairment is highly dependent on the setting. Community samples are more heterogeneous regarding to the etiology of cognitive deficits, given the higher representation of symptoms attributed to medical and psychiatric causes. In contrast, the proportion of subjects with underlying AD pathology tends to higher in tertiary services and specialized memory clinics, where most attendees are actively seeking diagnosis and treatment for their symptoms. Therefore, the diagnosis of cognitive impairment in community samples may favor sensitivity in detriment of specificity; conversely, the positive predictive value of the diagnosis tends to be higher in patients attending memory clinics. A good illustration of this problem was published by Stephan et al. , who shoAmong the various definitions that have been proposed to ascertain the clinical signs and symptoms attributed to the earliest stages of dementia, the Mayo Clinic description of MCI, launched by the seminal works of Petersen and collaborators , is perhSeveral other clinical and epidemiological investigations have also demonstrated that patients with MCI progress more often to AD or to other dementias than older adults without objective evidence of cognitive impairment. However, a substantial variation in the annual progression rates from MCI to AD is observed across studies, ranging from low estimates of 3% to very high estimates of 40% to 50% in samples defined according to the Mayo Clinic diagnostic criteria for MCI ,26. SeveThe prognostic value of the MCI subtypes is an important issue on debate. The early definition of amnestic MCI supported the notion that the patients would present at the early stages of AD with signs of episodic memory impairment and progress linearly to a full-blown dementia syndrome. A similar assumption was attributed to other MCI subtypes and respective  outcomes  Figure . NeverthEarly studies assumed a linear trend between healthy cognition to MCI and dementia in older adults. These notions were based on analytical approaches that used time to event or last observation carried forward. Despite useful to determine conversion rates, these studies were not informative of the pattern of transitions between different clinical states. A different analytical strategy based on the Markov Chain model addressed the transitions between intact cognition, dementia and death in a subset of the Nun Study . This moTherefore, the characterization of functional impairment is critical to establish the threshold between MCI and incipient dementia. Clinical and epidemiological studies have shown that patients with MCI may present subtle impairment in complex, instrumental activities of daily living (IAVDs), albeit not sufficient to impair independent living -38. ThisThis is important because the characterization of mild deficits in IAVDs in patients with MCI may hold a prognostic significance . The objective evaluation of functionality has so far been neglected in the diagnostic investigation. It normally relies on the subjective report of patients and caregivers, or on the administration of functional scales to caregivers. There are several sources of bias in this form of assessment, namely the cognitive state of caregivers, the pattern of relationship between the patient and caregiver, their mood state and personality characteristics ,41. ThusAs reviewed above, the concept of MCI may be sensitive to identify subjects that may develop AD/dementia, since most, if not all, individuals with predementia AD will present, at some point of the progression curve, with a long period of mild cognitive deficits prior to the onset of dementia. Nevertheless, as currently conceived, the clinically oriented diagnostic criteria for MCI yield a heterogeneous group of patients with distinct short-term and long-term outcomes. In other words, the specificity and the predictive value of the MCI diagnosis are low, and the cross-sectional identification of cases of prodromal AD may not reach adequate diagnostic accuracy if based solely on clinical tools . Rather,The development of biomarker research in AD is a good example of the successful effort to translate the knowledge of key pathophysiological mechanisms of the disease into clinical applications. A biomarker is a characteristic that can be measured and evaluated as an indicator of the pathogenetic processes, or to ascertain the effect of pharmacological interventions on predefined biological cascades . The ide42), total Tau (T-Tau) and phosphorylated Tau (P-Tau). AD patients characteristically display low concentrations of Aβ42 and high concentrations of T-Tau and P-Tau. This pattern of CSF biomarkers is commonly referred to as the 'AD signature' in the CSF. The aforementioned biomarkers reflect core pathophysiological features of the disease [42 and increased P-Tau are more specific to AD. Aβ42 is a byproduct of the abnormal processing of the amyloid precursor protein (APP) leading to amyloidogenesis and formation of neuritic plaques. In addition, decreased concentrations of Aβ42 likely reflect its deposition in plaques, preventing its clearance through the CSF P-Tau illustrates the cytoskeletal changes that arise from the deregulation of microtubule homeostasis and ultimately cause axonal dysfunction and neuronal death. This marker is more specifically associated with AD, given the central role of Tau hyperphosphorylation in the formation of paired helical filaments (PHFs) and neurofibrillary tangles [The CSF may be considered an ideal source for viable biomarkers in AD. It is in intimate contact with the cerebral tissue, and pathological changes in the brain are often reflected in the CSF . Among s disease , and hav disease -49. Incr tangles .To date, over 100 studies have been published to support the notion that this AD-positive CSF pattern has good diagnostic accuracy to distinguish between normal ageing and AD (> 85%) and a positive predictive value (> 90%) to determine the dementia outcome in patients with MCI . HoweverHowever, a few methodological limitations need to be overcome before this knowledge can be translated into practical clinical practice. Although the determinations of CSF concentrations of these biomarkers using enzyme-linked immunosorbent assay (ELISA) or multiplex techniques  have low coefficients of intralaboratory variability (5% to 10%), the high interlaboratory variation (20% to 30%) is a major obstacle for the comparison of data generated in different settings. Multiple sources of bias include preassay conditions , intra-assay conditions (different methods and protocols for the determination of the concentrations of biomarkers), and post assay variations  . This siper se, play a critical role triggering early pathological events of the amyloid cascade. High levels of Aβ oligomers are observed in the brain and in the CSF of patients with AD, underlining their potential for the early diagnosis of the disease [et al. [42 in the CSF of patients with AD, since the presence of Aβ oligomers can interfere with the analyses of the peptide by conventional methods, causing underestimation of Aβ levels due to epitope masking [New technologies targeting Aβ oligomers in the CSF will add important insights in this field in forthcoming years. The neuropathology of AD has been linked to the accumulation of non-fibrillar forms of neurotoxic Aβ oligomers. There is evidence that soluble Aβ oligomers, more than amyloid fibrils  disease . In a re [et al.  showed t masking . Therefo masking .in vivo intracerebral imaging of amyloid and Tau.The substantial development of neuroimaging technologies in the last decade has contributed decisively to the search for non-invasive methods to ascertain the pathological changes that evolve in the AD brain. These advances result from new protocols for the analysis of structural imaging   and funcStructural changes in the brain in AD are mostly represented by global cerebral volumetric reduction, increased ventricular volumes and regional atrophy in structures of the medial temporal lobe  . TopograWith respect to functional neuroimaging, the main metabolic changes observed in AD are global reductions in cerebral metabolism and perfusion as shown by FDG-PET and SPECT scans. These changes are observed in the temporoparietal junction, temporal, parietal and frontal lobes, hippocampal formation and posterior cingulate cortex ,76. As iin vivo within the brain is undoubtedly a major achievement in the field AD biomarker research. The first compound to be developed for human experimentation was the 'Pittsburgh Compound B' (PiB) [11C-labelled compound that binds intracerebral Aβ in mature amyloid plaques [18F-BAY94-9172 [The development of new technologies to visualize and quantitate Aβ and Tau deposits B' (PiB) , which i plaques . Other cY94-9172 , and theY94-9172 .42 in patients with mild AD as compared to controls [In AD, there is an increased global cortical and regional retention of PiB and other compounds, particularly in the cingulate, temporal, parietal and frontal cortices . Studiescontrols ,90.As observed in other neuroimaging modalities, the PiB retention rates are also increased in patients with amnestic MCI, albeit less than in AD patients. Positive PiB scans predict conversion, and PiB retention  correlates with cognitive performance ,92. In aA well defined pattern of CSF and imaging biomarkers can be characterized in AD. These biomarkers reflect core pathological changes that evolve in the prodromal phase of AD, including the predementia, and presumably the presymptomatic, stages of the disease. AD-related biomarkers identify with good accuracy non-demented patients with mild cognitive dysfunction who will ultimately progress to dementia, differentiating converters from healthy individuals and subjects with stable, non-progressive cognitive deficits. In addition, AD biomarkers may help to discriminate, although with lower accuracy, slow from rapid converting cases of MCI. The main biomarkers under investigation and their relationship with the pathological process in AD can be grossly subdivided into two main categories: (i) those reflecting core neuropathological changes of AD at the molecular level , and (ii) downstream biomarkers reflecting secondary changes to brain structure and function, namely volumetric and metabolic changes to temporomedial structures Table .In addition to providing biological support to the clinical diagnosis of AD, the establishment of biomarker technology has also favored the development of other important areas of research. First, the use of biomarker information can add important benefits to intervention trials, particularly with pharmaceutical compounds with disease-modifying properties. AD-positive biomarkers can be regarded as stringent inclusion criteria, defining more homogeneous samples of patients and therefore increasing the probability of success of randomized clinical trials; furthermore, the longitudinal reassessment of biomarkers can be viewed as a way to monitor specific biological outcomes of interventions with antidementia drugs, or to define proof-of-concept mechanisms of action of candidate drugs.Secondly, given the long preclinical phase of AD, another potential use of biomarkers is the characterization of early signs of the disease in presymptomatic stages of the process. Evidence from epidemiological and autopsy studies support the hypothesis that there is a temporal lag of approximately a decade between significant accumulation of amyloid in the brain and the clinical onset of dementia. The percentage of amyloid-positive normal individuals detected at one given age closely parallels the percentage of individuals diagnosed with AD dementia a decade later . In a loFinally, the actual prevention of dementia will be a tangible goal when the aforementioned challenges have been accomplished. In other words, the identification of individuals at high risk for developing dementia  and the effective treatment with pharmaceutical compounds with disease modifying properties will ultimately preclude (or at least attenuate) the subsequent neurodegeneration and eventual cognitive decline Table .Individuals with mild cognitive deficits do display signs of AD pathology, since approximately 50% are already in Braak neurofibrillary stage III or higher, and 20% are likely to be in more advanced stages of neuropathology . It is lThe measurement of AD-related biomarkers in the CSF or by neuroimaging methods improves diagnostic accuracy and predictive value of the clinical classification of patients according to the definition of MCI. The characterization of early clinical signs of AD (compatible with episodic memory impairment) with the support of one or more well established biomarkers has been recently proposed as the core feature required for the diagnosis of AD in the predementia stages . This suIn spite of the relevant contribution of clinical and biomarker research in the early diagnosis of AD, or even the characterization of the disease in asymptomatic or minimally symptomatic individuals, the use of these technologies raises the possibility of misidentification of cases. The incorrect classification of individuals as being at high risk for AD may lead to undue alarm and concern, in addition to unnecessary interventions. Therefore, before biomarker profiles are used in the general population, high specificity should be demonstrated in multiple populations. For the time being, the careful and comprehensive clinical judgment is mandatory to guide therapeutic decisions, even though the diagnostic hypothesis may be strongly reinforced by a positive biomarker. In the prospect that safe and effective, experimentally validated disease-modifying therapies become available in the near future, the reliable early detection of AD in the general population will become an essential tool in the prevention of this illness ,114.The authors declare that they have no competing interests.The authors contributed equally to the selection and discussion of the literature reviewed in this work. The authors participated equally in the conception and preparation of the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1741-7015/8/89/prepub


The majority of tinnitus cases are related to cochlear dysfunction, leading to altered peripheral input to the central auditory system . These aTherefore we developed a simplified version where we could efficiently implement models of short-term and long-term synaptic plasticity. The structure and organization of the simulation was adopted from the Hodgkin-Huxley-type model , i.e. itImportantly, the model largely showed the same results as the previous model, when we switched off all short- and long-term plasticity mechanisms. The tinnitus cluster shows an increased basic level of activity in the absence of input and, moreover, a diminished increase of activity during sound presentation of this particular frequency. Again a change of the ratio between excitatory and inhibitory weights towards more excitation and less inhibition in the TC results in a normal increase of activity during sound presentation.Including the plasticity mechanisms results in an increase of excitatory weights over time in the TC. This results in a higher firing rate in TC and the tinnitus cluster shows an even higher basic level of activity during absence of sound which almost reaches the activity level during sound presentation before plastic changes. Furthermore, the 'pathological region' shows a dramatically increased synchronicity in firing behaviour which is also associated with tinnitus manifestation . FurtherThe presented simulation shows that synaptic plasticity facilitates processes that are believed to constitute the beginning of tinnitus manifestation. Our neurobiologically plausible simulation is an encouraging starting point for further modeling of the development of tinnitus, particularly due to its flexibility and computational efficiency.


The formation of marine phosphatic mineral deposits remains incompletely understood, despite decades of research. The involvement of bacteria in this process has long been suspected, and both modern and ancient associations between bacteria and phosphorites have been recorded. Only recently has a specific bacterial metabolic process associated with the formation of phosphorites been discovered. Recent studies demonstrate that polyphosphate utilization by sulfide-oxidizing bacteria results in the rapid precipitation of apatite – providing at least a partial mechanism to explain the close spatial correlation between accumulations of sulfide-oxidizing bacteria and modern phosphorites. Possible fossilized bacteria are known from ancient phosphatic mineral deposits. Potentially, the fossilized cells represent the remains of bacteria that induced the formation of those phosphorites. However, robust criteria for the recognition of these bacteria have yet to be identified. As a li42- . The ubi42- .5(PO4)3, or its more complex form carbonate fluorapatite (CFA)  . Phosphowt% P2O5 . Phosphawt% P2O5 . The diswt% P2O5 . Since twt% P2O5 . But whaFigure 1). The process of phosphogenesis begins with the precipitation of CFA or its metastable precursors within the top few centimeters of marine sediment. It is generally thought that disseminated CFA is then concentrated through a variety of sedimentological processes such as reworking . The rate of phosphate released by Thiomargarita in the laboratory was calculated to be sufficient to explain the mineral and pore water phosphate enrichment observed in phosphogenic sediments off Namibia   . Severaligure 2) . For exaigure 2) . Howeverigure 2) . HoweverIt seems that we are in the midst of a revolution in our understanding of the origins of phosphatic mineral deposits. Knowledge gained in fields as varied as wastewater treatment, geochemistry, and paleontology have all strengthened the argument for the role of microbes in the precipitation of apatite and the formation of phosphorite rock. A compelling mechanism for the concentration of phosphate in pore waters where apatite is actively precipitating has been discovered in the form of polyphosphate utilization by vacuolated sulfide-oxidizing bacteria. Many gaps remain in our understanding of the complete story. The processes and substrates involved in the transition from pore waters enriched in phosphate to the precipitation of apatite precursors remain poorly constrained. Eventual cultivation of vacuolated sulfide-oxidizing bacteria may allow for the experimental recreation of microbially mediated apatite precipitation in the laboratory. The rapid advancement of genomic and metagenomic approaches may bring us closer to understanding the genes involved in polyphosphate utilization, or help us understand community interactions in sediments where phosphogenesis is occurring.Fossilized microbes have been identified in ancient phosphorites, and potentially some microfossils from ancient settings record the presence of sulfide-oxidizing bacteria. However, morphological criteria can frequently be insufficient for the identification of specific bacterial ecotypes. Future discovery and confirmation of evidence for microbially mediated phosphogenesis in the ancient rock record would be aided by the identification of diagnostic chemical signatures of microbes, such as lipid biomarkers, or signatures of the microbially mediated phosphatization process itself – perhaps a distinctive isotopic signature in phosphate-associated geochemical species. Additional investigation into the role of changing geological and oceanographic conditions in the production and preservation of ancient phosphorites, as well as sedimentary basin analysis, may reveal potentially relevant paleophysiographic features such as cratonic placement and orientation, or detailed isotopic characterization of phosphatic lithologies.Phosphorite formation requires interactions among many aspects of the geosphere and biosphere, and a comprehensive understanding of the processes involved will require a multi-disciplinary approach applied to both modern phosphogenic environments and their ancient analogs. The results could have important ramifications for the exploration and sustainable management of this mineral resource so intimately connected to the global phosphorous cycle and to modern agriculture.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Immune-mediated rejection of human cancer is a relatively rare but well-documented phenomenon. Its rate of occurrence progressively increases from the occasional observation of spontaneous regressions to the high rate of complete remissions observed in response to effective treatments. For two decades, our group has focused its interest in understanding this phenomenon by studying humans following an inductive approach. Sticking to a sequential logic, we dissected the phenomenon by studying to the best of our capability both peripheral and tumor samples and reached the conclusion that immune-mediated cancer rejection is a facet of autoimmunity where the target tissue is the cancer itself. As we are currently defining the strategy to effectively identify the mechanisms leading in individual patients to rejection of their own tumors, we considered useful to summarize the thought process that guided us to our own interpretation of the mechanisms of immune responsiveness. The first evidence that T cells can recognize cancer was based on the description by Wolfel et al.  of tumorOne category of TAs included melanoma differentiation antigens (MDA) whose expression is shared by melanoma cells and normal epithelial melanocytes. Another category includes proteins whose expression was associated with the progressive de-methylation of cancer cells; as these non-mutated proteins were expressed selectively by germ line cells in the testes and cancer cells, they were named cancer testing antigens (CTA).The identification of MDAs and CTAs and their respective epitopes associated with specific HLA molecules spurred interest in using these molecules and their derivatives for TA-specific active immunization . An incrDespite the large number of trials vaccinating patients with TAs, results have been in general disappointing , 10, 11,Anti-cancer vaccination efforts consistently elicited expansion of TA-specific memory T cells in the peripheral circulation, but this was rarely accompanied by cancer regression , suggestLee et al.  documentmilieu conducive to their reactivation comparable to that simulated in vitro by re-stimulation with TA in the presence of IL-2 [While the work of Lee and other groups focused on spontaneously occurring TA-specific T cells, others analyzed the type and function of vaccine-elicited T cells documenting that naturally occurring TA-specific immune responses could be consistently enhanced by immunization , 29. Con of IL-2 ? While m of IL-2 . It shouEvolution under selection implies that forceful negative pressure is imposed upon malleable phenotypes. To explain the co-existence of a cognate immune response against cancer with its concurrent growth, immune selection is often invoked , 32. ThiDirect observation of the tumor microenvironment may obviate for the need of hypotheses , 43. As It soon became apparent, however, the classical approaches to the study of tumors were not suitable. Most studies utilized excisional biopsies, which provide optimal quantity of tissue and allow its morphological assessment. However, because the tumor is removed, serial sampling of the same lesion for dynamic studies cannot be done. Moreover, no direct correlation can be performed between the findings obtained studying the excised material and the response to immunotherapy of concomitant metastases left in the patient. The assumption that removed tumors are representative of those left in the patient as targets of therapy was soon proved inaccurate; the study of synchronous metastases demonstrated significant variability among most markers evaluated . We, the111-labeled adoptively transferred TILs is necessary for clinical response [Localization within tumors of indiumresponse ; howeverSince TIL localization in the target organ is necessary for tumor rejection, we tested whether vaccine-induced T cells reached the tumor site. Kammula et al.  applied Several studies suggest that tumors produce immune regulatory molecules that could suppress the function of T cells. Applying FNA biopsies, we assessed in pre-treatment samples the expression of cytokines with potential regulatory effects . SurprisIt is logical that the success of TA-specific vaccination is predicated upon the level of expression of the target TA by cancer cells. We, therefore, measured by FNA in pre- and post-treatment metastases the expression of TA relevant and irrelevant to the vaccine administered . The anaThe dynamic approach to the study of immune responsiveness had, by the end of the 1990s, crushed several myths. Hundreds of modulatory mechanisms that could hamper immune responsiveness could be postulated but such number was too high to be realistically tackled by future studies with a minimalistic approach. Around that time, whole-genome transcriptional assays enter the scene of clinical investigation . The hypThe first attempt to address at the whole genome level the determinism leading to tumor rejection was an analysis of melanoma metastases biopsied before and after treatment with TA-specific vaccination and concomitant systemic administration of IL-2 . AnalysiIn a separate study, we evaluated the mechanism of action of systemic IL-2 administration by sampling melanoma metastases before and during treatment. This study demonstrated that the mechanism of action of IL-2 is an indirect activation of macrophages mediated by a cytokine storm released by circulating IL-2 receptor-bearing cells . The effIn 1969, Jonas Salk  hypothesThe ICR axiom describes how TSD occurs independent of its cause; in other words, the ICR dictates “how” but not “why” rejection occurs. However, the definition of a necessary pathway clarified the premises for the identification of its causes. It became clear that the lack of rejection of tumors during immunotherapy is due to insufficient stimulation of immune responses at the tumor site rather than to the escape of tumors from a fully activated immune response. Analysis of patients with melanoma experiencing a mixed responses  and compPerhaps, the most important contribution offered by the ICR concept in deconvoluting the determinism of tumor rejection is the provision of a road map defined by evidence-based hypotheses. Identification of a specific group of genes, whose activation is necessary for TSD, leads to the analysis of the role of IRF5 polymorphism in melanoma immune responsiveness. This study was based on the premise that, if the ICR applies to autoimmunity and if cancer rejection represents an aspect of autoimmunity, genes relevant to the development of autoimmunity ought to influence the immune biology of cancer. IRF5 plays a significant role in the modulation of several autoimmune diseases including systemic lupus erythematosus (SLE). We recently observed that the same polymorphisms protective against the development of SLE predict non-response to adoptive transfer of TILs (unpublished own data). Similarly, appreciation for the central role played by the CXCR3/CCR5 cluster in mediating TSD leads us to the investigation of its expression by TILs. Integration of germ line, transcriptional, and protein expression data brought to the formulation of a protein prediction model strongly predictive of treatment outcome (unpublished own data). It is important to note that in this study, the expression of individual receptors was not highly predictive of immune responsiveness but the combined over- or underexpression was strongly pointing to the need to look at the biomarkers of immune responsiveness not as individual entities but in accordance with their combined function. Importantly, this second-generation, evidence-based, and hypothesis-driven studies enlightened an underappreciated fault of current bioinformatics approaches applied to the identification of biomarkers of immune responsiveness. This study demonstrated that individual, univariate approaches bear, when examined individually, very little predictive value but the combination of factors integrated according to a logical stream may progressively break the code governing the algorithm of immune responsiveness.The relative weight played by the host’s genetic background, the somatic alterations acquired during the neoplastic process, and the influence of environmental factors in determining immune responsiveness is unclear. Observations performed during the last two decades strongly suggest that it is a combination of the three that determine immune responsiveness . It is lIn the same manuscript where the delayed allergy reaction was described, Jonas Salk  also sta


Metronidazole (MTZ) is commonly used as an antibacterial and antiprotozoal drug. Various doses of MTZ have been reported to inhibit spermatogenic activityand sperm indices.In this experimental study, dose-dependent effects of MTZ onthe structural and functional integrity of the testis and accessory reproductive organshave been investigated. Adult male mice of Swiss strain were administered orally withMTZ at the doses of 250 mg/kgBW/day and 500 mg/kgBW/day for 28 consecutive daysto study the changes in the testis, epididymis, seminal vesicle, sperm indices and fertility.Reversal effects of the drug were also studied on the same mice, 42 days after cessationof the treatment.Therapeutic dose of MTZ (250 mg/kgBW/day) neither altered the weights ofthe testis, epididymis and seminal vesicle nor their histoarchitecture and sperm indices. The drug at the high dose (500 mg/kg BW/day) caused significant reductions in theweights of the testis and epididymis. Histoarchitecture of the testis and epididymis at thehigh dose revealed marked regressive changes while that of seminal vesicle remainedunaffected. Significant reductions were noticed in the motility, viability and count ofepididymal spermatozoa while the concentrations of epididymal sialic acid and seminalvesicular fructose remained unaltered after the treatment. No significant changes werenoticed in the mating ability as well as in the level of serum testosterone in the treatedmice. Fertility of the male mice treated with high dose of MTZ declined markedly leading to an increase in pre- and postimplantation loss while a significant decrease wasnoticed in the number of live blastocysts in females impregnated with such males. MTZinduced changes in the male reproductive organs and fertility were reinstated 42 daysafter cessation of the treatment.High dose of MTZ induced reversible deleterious effects on the male reproduction and fertility. The increase in incidences of infertility in mendue to frequent use of a number of therapeuticdrugs has made efforts to study their untoward sideeffects on the male reproduction. Various drugsused for treating diseases are reported to causemale infertility , 2. AmonHelicobacter pylori infection, amoebiasis, giardiasis, trichomoniasis, bacterial vaginosisand several other anaerobic bacterial and parasiticinfections. However, for the treatment of severalcomplications like Chagas disease, Crohn’s disease, osteomyelitis, endocarditis, deep neck infection, joint infection and liver abscess, this drug isadvised to be consumed for 4-8 weeks. Inspite ofits long-term clinical use, untoward side effects ofMTZ on the male fertility has been studied in laboratory rodents , a drug of first choice,recommended by the clinicians to be consumedat maximum for seven to ten days for the treatment of  rodents , 7, 8. A rodents , 9, 10.Quantitative studies have indicated marked alterations in the number of germ cells at stage I, Vand XII following intraperitonial administration of130 mg/kgBW/day of MTZ for seven days in mice while thFrom the foregoing it is clearly seen that MTZ atvarious doses impairs fertility in the males by inhibiting spermatogenic activity and sperm indices.However, a detailed study regarding the effects oftherapeutic dose of MTZ for long duration, suchas for 4-8 weeks on the male reproductive organsand fertility is still required. Therefore, the aim ofthe present study is to investigate the effects of thetherapeutic and high doses of MTZ on the testis,epididymis, seminal vesicle and fertility as well ason the secretory activities of the latter two organs.For the safety evaluation of the potential effect ofthe drug on the male reproductive organs, a studywith a dose higher than the therapeutic one may beconsidered in a non clinical trial. The study alsodeals with the withdrawal effects of high dose ofMTZ, 42 days after cessation of the treatment. In this experimental study, fifty Swiss strainadult (12 weeks old) male mice weighing about25-30 g were used for the present investigation.The animals were housed under standard laboratory conditions and maintained on pelleted dietand water ad libitum. Approval from the AnimalEthical Committee, Banaras Hindu University,Varanasi, India was obtained for the animal studyplan (No. Dean/11-12/CAEC/263).Group I Untreated controlsGroup II Vehicle-treated controls (distilled water)Group III Administration of MTZ (250 mg/kgBW/day) for 28 daysGroup IV Administration of MTZ (500 mg/kgBW/day) for 28 daysGroup V Administration of MTZ (500 mg/kgBW/day) for 28 days followed by sacrificing the animals 42 days after cessation of the treatment.After recording the initial body weights, all theanimals were divided into five groups of ten eachand treated as follows:MTZ  was dissolved in doubledistilled water and administered orally. Thehuman therapeutic dose of MTZ was selectedand translated to mice . The dosAfter recording the final body weights the animals were sacrificed by cervical dislocation.Among ten animals from each group, five animalswere used for the histological studies and spermassessment while the other five were used for biochemical studies, fertility test and serum testosterone level. Blood was collected by cardiac punctureto measure the level of serum testosterone. The reproductive organs were dissected out, blotted freeof blood and processed for the following studies:Wet weights of the testis, epididymis and seminal vesicle were recorded to calculate the gonadosomatic index by using the following formula:Gonadosomatic Index (GSI)= ×100.Bouin’s fixed testis, epididymis and seminalvesicle were dehydrated and embedded in paraffin. Sections of 5 μm thickness were taken fromthe mid portion of each testis, all the three regionsof epididymis and seminal vesicle, dehydrated ingraded series of alcohol and stained with PeriodicAcid Schiff reagent followed by counterstainingwith Ehrlich’s Hematoxylin.Frequency of the stages was determined fromone cross section of the testis of the five animalsin each group. All the seminiferous tubules within a cross section of the testis were examined at×40 and classified according to the stages of thecycle. The stages of the seminiferous tubules wereclassified according to the method of Hess andFranca . Due to The diameter of the seminiferous tubules wasmeasured using ocular micrometer at ×40 objective piece.Concentrations of epididymal sialic acid andseminal vesicular fructose were estimated usingthe methods of Aminoff  and LindCauda epididymidis of five mice in each groupwas minced thoroughly in the physiological normal saline at 37˚C and used for the assessment ofmotility, viability and count according to the WHOLaboratory Manual . The speEvaluation of sperm abnormality was basedon the criteria of Wyrobek and Bruce  andZaneSerum testosterone was measured by ELISA,as described in the instructions provided in the kit.Each male was caged with two proestrus females overnight and according to presence ofvaginal plug and implantation sites in females,the mating ability and fertility of the males wereassessed respectively. The females were sacrificed by cervical dislocation on the fifteenth dayof cohabitation with males. The ovaries wereremoved to count the number of corpus luteum.To determine the total number of implantationsites, the dissected out uteri were placed in 10%ammonium sulfide solution, which stained thehemosiderin pigment of resorbed implantedsites blue-black . The numCorpus luteum – [number of resorbed implants+ number of live implants + number of dead implants]Postimplantation loss was equal to the totalnumber of resorbed and dead implants.All the data were analyzed statistically by oneway ANOVA followed by Newman-Keul’s test. Body weight and number of live implants as wellas pre- and postimplantation loss were analyzedusing Student’s t test. Values were considered significant at p<0.05.No significant differences were found betweenthe initial and the final body weights of the MTZtreated mice and the controls at therapeutic andhigh dose . Administration of MTZ at the therapeuticdose did not induce significant changes in theweights of the testis and epididymis while thedrug at the high dose resulted in significant reductions in the weight of these organs as compared with the controls. Forty two days aftercessation of the treatment, weight of the organsrecovered to the control values. Administrationof MTZ at any dose did not induce significantreduction in the weight of the seminal vesiclecompared with that of controls . The testis of untreated and vehicle-treatedcontrols  showed nQuantitative analysis of the spermatogenic cyclerevealed no alterations in all the stages of the seminiferous tubules in the testis of mice administered withtherapeutic dose of MTZ as compared with the controls. In contrast, a significant decrease was observedin stages I-VIII after high dose of MTZ-treatment ascompared with the controls . TreatmeTherapeutic dose of MTZ treatment did not induce any alteration in the diameter of the seminiferous tubules while a significant decrease in thesame was noted in the testis of mice administeredwith high dose of the drug as compared with controls . By 42 dThe epididymis of the untreated and vehicletreated controls exhibited normal histologicalfeatures. In the Swiss mice, five segments (I-V)were noticed in the epididymis. Segments I-IIIconstituted the caput ; segmentTreatment with MTZ at any dose did not causeany alteration in the histoarchitecture of the seminal vesicle as compared with the control .Administration of MTZ at any dose did not induce significant alterations in the concentrationsof sialic acid in the epididymis and fructose in theseminal vesicle .Therapeutic dose of MTZ did not cause significant reductions in the motility, viability and countof epididymal spermatozoa. By contrast thesesperm indices declined significantly in mice administered with high dose of MTZ. Percentage ofabnormal spermatozoa increased in MTZ-treatedgroups, though, the values were not significant.Withdrawal of the treatment, however, resulted inmarked recovery in motility, viability and count ofspermatozoa in the epididymis comparable to thatof control .No significant change was found in the level ofserum testosterone caused either by therapeutic orhigh dose of MTZ as compared with the control.Mating ability of all the treated males remained almost unaffected comparable to that ofthe controls. Marked reduction was noted in thefertility of the males treated with high dose ofMTZ; 67% of treated males became infertile after the treatment. Fertility of the virgin femalesimpregnated with such males also declined by75% . In the Oral administration of MTZ at therapeuticand high doses did not affect body weight ofall the animals. However, significant reductionwas noticed in the weight of the testis in themice treated with high dose of MTZ. This isconsistent with the findings reported in rats andmice -11, 13. The histological study revealed that the therapeutic dose 250 mg/kgBW) of the drug did notcause marked alterations in the seminiferoustubules when administered for 28 days whilethe drug at high dose (500 mg/kg BW) for thesame duration induced noticeable regressivechanges in the seminiferous tubules resulting inthe suppression of spermatogenic activity. McClain et al. have reported severe degenerationof the seminiferous tubules with appearance ofgiant cells in their lumina in the testis of rat exposed with MTZ at the dose of 400 mg/kgBWfor 8 weeks. These authors have also reportedpartial recovery in spermatogenic activity threeand a half months after cessation of the MTZtreatment . However0 mg/kgBWThe spermatogenic inhibition as noticed inour study is reflected by alterations in the frequency of different stages as well as diminution of the germ cells at stage VII of the spermatogenic cycle. Earlier studies have shownthat intraperitonial administration of 130 mg/kgBW of MTZ for 7 days in CFW mice causedno alterations in the number of stages in theseminiferous tubules while the number ofcells in stages I, V and XII was significantlyincreased . QuantitA significant reduction in the weight of theepididymis in high dose of MTZ-treated miceis consistent with that reported by others ,12, 13.MTZ is reported to inhibit the sperm motilityat different doses in mice and rats , 7, 11.Significant reduction in the sperm count noticed after high dose of MTZ treatment is consistent with the earlier findings , 11, 12.In contrast to the reports of El-Nahas and ElAshmawy  and SohrMTZ administration at any dose did not affect the mating ability of the mice. However,marked reduction was noticed in the fertility ofthe males administered only with high dose ofMTZ resulting in decrease in the fertility of females impregnated with such males. A consistent finding is reported in the rat . DecreasHigh dose of MTZ induced rrelatively reversibledeleterious effects on male reproduction and fertility, attributable to the direct action of MTZ on thespermatogenic activity rather than through serumtestosterone depletion.


Plasmodium falciparum parasites has greatly impacted malaria control, especially in highly endemic areas of Africa. Since chloroquine removal a decade ago, the guidelines to treat falciparum malaria suggest combination therapies, preferentially with an artemisinin derivative. One of the recommended partner drugs is amodiaquine, a pro-drug that relies on its active metabolite monodesethylamodiaquine, and is still effective in areas of Africa, but not in regions of South America. Genetic studies on P. falciparum parasites have shown that different pfcrt mutant haplotypes are linked to distinct levels of chloroquine and amodiaquine responses. The pfcrt haplotype SVMNT (termed after the amino acids from codon positions 72-76) is stably present in several areas where amodiaquine was introduced and widely used. Parasites with this haplotype are highly resistant to monodesethylamodiaquine and also resistant to chloroquine. The presence of this haplotype in Africa was found for the first time in 2004 in Tanzania and a role for amodiaquine in the selection of this haplotype was suggested. This commentary discusses the finding of a second site in Africa with high incidence of this haplotype. The >50% SVMNT haplotype prevalence in Angola represents a threat to the rise and spread of amodiaquine resistance. It is paramount to monitor pfcrt haplotypes in every country currently using amodiaquine and to re-evaluate current combination therapies in areas where SVMNT type parasites are prevalent.The loss of chloroquine due to selection and spread of drug resistant  Plasmodium falciparum isolates from Angola show the StctVMNT haplotype in the pfcrt gene" by Gama BE et al [The article "BE et al  providesBE et al  and a geBE et al , highliget al examined the prevalence of different haplotypes of the Plasmodium falciparum chloroquine (CQ) resistance transporter gene pfcrt, and the multiple drug resistance transporter pfmdr1, from patients in Angola with uncomplicated malaria in 2007. At that time the patients were treated with one of the two artemisinin combination therapies, artemether + lumefantrine or artesunate + amodiaquine (AQ), in accordance with the country's anti-malarial guidelines.Gama pfcrt haplotype often found in other countries including Brazil, India, Papua New Guinea, and the Philippines  of a CQ-resistant sistance  and the 0% of a Cin vitro responses to CQ, AQ, and its active metabolite monodesethylamodiaquine (MDAQ) from the P. falciparum genetic cross 7G8xGB4, between a CQ-resistant clone from South America carrying the SVMNT pfcrt haplotype and an African clone carrying the CVIET haplotype, showed that these haplotypes are linked to distinct AQ/MDAQ and CQ responses [P. falciparum infected samples collected in 2003 and 2004, revealed SVMNT haplotype prevalence of 0% and 19%, after the increased use of AQ indicating a strong and quick evolutionary force. This idea is also supported by another recent report from Afghanistan, where the prevalence of P. falciparum SVMNT type has been associated with AQ resistance [pfcrt haplotypes interact with AQ, MDAQ, and CQ is yet to be determined, but it may rely on their specific physicochemical characteristics such as amino acid side-chain volume, charge, and hydrophobicity [The analysis of the esponses . Parasitpfcrt haplotype. While regions in Africa and China where CVIET was the prevalent, if not exclusive haplotype, have been repopulated by CQ-sensitive parasites with the CVMNK haplotype after CQ removal [A greater fitness cost may be associated with parasites carrying the CVIET rather than the SVMNT  removal -13 regioP. falciparum parasites of the pfcrt haplotype SVMNT, which easily adapt with relatively little fitness cost. The monitoring of pfcrt codon positions 72-76 from P. falciparum infected patients in all countries using AQ in their treatment guidelines, regardless of the combination drug is crucial. An estimation of the current distribution of parasites with this haplotype and the consideration of complete removal of AQ from areas of SVMNT prevalence is important because of the resistance levels of SVMNT parasites and the likelihood that they will be as fit as the drug-resistant parasites from South America, where the treatment options of AQ as well as CQ have long been lost.It is essential to reiterate to the scientific community and government agencies the possibility of this hypothesis: AQ use results in the rapid evolution of 4-aminoquinoline resistant The continued use of AQ in combination therapies is dangerous in regions where resistant SVMNT parasites occur and threatens the selection of parasites resistant to the partner drug. All efforts should be made to monitor and to halt the selection of SVMNT parasites in Africa and develop new partners in effective combination therapies that will protect the anti-malarial arsenal.Pfcrt: P. falciparum chloroquine resistance transporter gene; CQ: chloroquine; AQ: amodiaquine; MDAQ: monodesethylamodiaquine.The authors declare that they have no competing interests.JMS and OT wrote the manuscript. All authors have read and approved the final manuscript.


Radiation enteritis is a significant complication of external beam radiotherapy (EBRT) to the pelvis, particularly in patients having high dose radiotherapy (>80 Gy) and in those with a low pelvic peritoneal reflection allowing loops of small bowel to enter the radiation field. Laparoscopic insertion and subsequent removal of a pelvic tissue expander before and after external beam radiotherapy is a relatively convenient, safe and effective method for displacing loops of bowel out of the pelvis. We report on a patient with prostate cancer who ordinarily would not have been a candidate for EBRT due to loops of bowel low in the pelvis. With laparoscopic insertion and subsequent removal of a tissue expander, he was able to have radiotherapy to the prostate without developing radiation enteritis. Prostate cancer is the second most common cancer in men. With the increasing use of primary radiotherapy for prostate cancer and improved survival, chronic radiation enteritis is an increasing problem occurring in over 20% of patients. The verLaparoscopic insertion and subsequent removal of a tissue expander before and after radiotherapy is a relatively convenient and minimally invasive procedure that may be an option for displacing loops of bowel from the radiation field.The patient was a 75 year old man with prostate cancer, confirmed by FNA to investigate a raised PSA. He had stage 2 disease with a Gleason score of 3+4, and required primary radiotherapy. He was relatively fit and healthy, with a BMI of 29. He had a previous upper midline laparotomy for gastric lymphoma, and open appendicectomy for perforated appendicitis, and a laparoscopic cholecystectomy. Radiation planning CT demonstrated a low pelvic peritoneal reflection with loops of bowel in the pelvis within the planned radiation field of the prostate Figure .These loops of bowel would not move out of the planned radiation field despite several manoeuvrers including extreme prone and Trendelenburg positioning, bladder filling, and use of an open table-top device (belly board). Laparoscopic insertion of a tissue expander into the pelvis to displace loops of bowel was his only option. No bowel prep was required. A 12 mm infra-umbilical incision was made and an open Hasson technique used to achieve pneumoperitoneum, with the placement of a 12 mm port at the umbilicus and 5 mm ports in both iliac fossa  lubricant and inserted via the 20 mm suprapubic port and placed laparoscopically in the pelvis, leaving the normal-saline inflation port attached externally.A TRD 500 ml Nagorg Figure  was then® needle inserted into the inflation port, the tissue expander was then filled with 350 ml of normal saline until the expander began to bulge against the retaining stitch  purse-string stitch was then sutured to the peritoneum of the sacral promontory, and anterior and side walls of the pelvis below the level of the common iliacs, and tied snug to keep the expander in the pelvis. With a HuberThe abdomen was then deflated of gas and the fascia of both the Pfannenstiel and umbilical port closed. The port of the expander was then placed in a small subcutaneous pocket and sutured to the fascia of the anterior abdomen. Skin incisions were closed in the usual manner. Subsequent CT confirmed adequate placement of the expander device in the pelvis with loops of bowel now well out of the pelvis and the planned radiation field Figure .His recovery was uneventful being discharged home without complication after opening his bowels. Two weeks later he went on to have external beam radiotherapy to his prostate (80 Gy in 39 fractions over 8 weeks), achieving a good response without any side effects or symptoms. Repeat CT prior to removal of the expander showed a well placed expander within the pelvis, with no evidence of radiation injury to small bowel or the prosthesis.The tissue expander was removed laparoscopically 6 weeks after completing radiotherapy using the same initial incisions, with a good cosmetic result. There were no adhesions to the silicone implant, and the PDA retaining string was intact, but easily broke with a gentle tug. These two factors facilitated its easy laparoscopic removal.Radiation enteritis causes considerable disability, and in many cases can be avoided. Any patient having external beam pelvic radiotherapy should have a planning CT, with particular attention given to those patients with a low peritoneal reflection, and loops of bowel within the planned radiation field. Methods of reducing injury to small bowel include multi-field conformal therapy with prior three dimensional planning where the profile of the radiation beam is shaped to fit the target. The delivery of intensity-modulated radiotherapy can also be adjusted and improves the ability of treatment volumes to conform to the shape of the tumour. Despite these techniques, loops of bowel still occasionally get injured from being in the radiation field. If available, brachytherapy or cryotherapy may be reasonable alternatives to external beam radiotherapy. Where external beam radiotherapy is the preferred or only option, various methods for removing small bowel from the radiation field exist.Conventional non-operative manoeuvres to remove small bowel from the pelvis at the time of giving radiotherapy include extreme prone or Trendelenburg positioning, bladder distension, abdominal wall compression or the use of an open table-top device (belly board). The response of such manoeuvres is not always reproducible. More extreme measures described only in case reports include the surgical insertion of a peritoneal dialysis catheter and creation of a temporary artificial pneumoperitoneum or ascitEarly surgical procedures to keep small bowel out of the pelvis were aimed at abdomino-pelvic partitioning, either with the use of native tissue or prosthetic material. Native tissue partitioning frequently involves the use of the peritoneum, bladder, uterine broad ligaments and omentum. In 1979, Freund described suturing the anterolateral peritoneum to the bladder and to the anterior rectum. In womeThere are many difficulties with partitioning techniques. Firstly, native tissue is frequently not sufficiently adequate or strong enough to achieve partitioning, and prosthetic materials run the risk of infection or adherence to loops of bowel or the creation of a fistula. Partitioning of the pelvis from the abdomen may also create an empty pelvic space. Loops of bowel may get caught beneath the partition resulting in an internal hernia and obstruction. The cavity beneath the partition may also fill with fluid, and this has the potential to become infected resulting in a chronic pelvis abscess.Pelvic-space occupying techniques avoid some of the problems inherent to partitioning techniques. In 1984, Russ described using an omental pedicle flap based on the left gastroepiploic vessels, which is placed along the left para-colic gutter with the distal tip packed into the pelvis. This isNormal saline filled silicone tissue expanders are easy to insert and remove and have the benefit of being non-adherent to both peritoneum and small bowel, as well as radioresistant to degradation, and when filled with normal saline, are similar in density to human tissues, therefore do not alter the isodose distribution of radiotherapy. In 1983, Sugarbaker first described the open insertion of a normal-saline-filled silicone breast implant into the pelvis to exclude small bowel from the pelvis to prevent injury from post-operative radiotherapy[Early experience with tissue expanders found that complications were more common when large expanders where left in the pelvis long term, with the potential for bladder, ureteric and iliac vessel compression. Heaviness is a common complaint of very large expanders. Deep veOurs is the first report in the literature of a totally laparoscopic insertion and removal of a tissue expander prior to and following primary prostatic radiotherapy. In this case, a much higher dose of 80 Gy radiotherapy was given. Previous major surgery was not a contraindication to this procedure. In our case, a conventional 500 ml normal-saline-filled silicone tissue expander without suture tabs, was used, and it was kept in the pelvis by means of a polydiaxanone (PDA) purse string suture. This monofilament has a tensile-strength half life of 5 weeks, with significant degradation of the suture at 10-12 weeks. Therefore removal of the expander was performed easily by gentle traction alone. However there is a risk with dissolvable sutures of tissue expander migration, therefore a non-dissolvable suture may also be appropriate. The choice of a conventional sized expander and the avoidance of overfilling were because of literature reports of the risks of ureteric and iliac vessel compression.The ease, simplicity, reversibility, and minimally invasive nature of laparoscopic tissue expander insertion are its main appeal. It should be considered as an option for excluding small bowel from the pelvis prior to radiotherapy of the prostate.Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.GM wrote the manuscript, KW did literature review and organised planning CT and radiotherapy; DK inserted and removed the tissue expander and supervised writing of manuscript. All authors read and approved the final manuscript.


Reconstruction of the perineum and pelvic cavity in continuity is an uncommon and difficult challenge. This case describes a 66-year-old man who presented following recurrence of a Dukes’ B rectosigmoid adenocarcinoma that had been treated nine years previously by anterior resection, 5-fluorouracil and radiotherapy. His recurrent disease was treated with radical pelvic exenteration with formation of an end colostomy and urinary ileal conduit.A post-operative pelvic collection necessitated incisional drainage via the perineum. This resulted in a perineal defect in continuity with the pelvic cavity, neither of which healed in spite of alternate day packing with antiseptic dressings. The perineum and cavity were reconstructed successfully with a microvascular transfer of the latissimus dorsi using the primary gracilis pedicle as recipient donor vessels. Reconstruction of the perineum is most commonly facilitated using local flap options such as the gracilis, gluteus, rectus abdominis, anterolateral and posterolateral thigh flaps. For smaller defects, the gracilis (a thin strap muscle with little bulk) is often adequate and can facilitate a large paddle of skin in some cases. In the case of larger defects, the rectus abdominis flap is the most commonly employed in gynaecological reconstructions of the perineum. However, formation of a colostomy, ileal conduit or even laparotomy alone can damage the perforating vessels needed for the rectus abdominis flap. In the absence of these flaps to hand, the latissimus dorsi (LD) provides an excellent substitute as well as substantial coverage for these larger defects.Based on a literature review, it is evident that the use of free LD myocutaneous flaps for perineal and pelvic reconstruction is uncommon. Five articles in the English language were found in the literature and these described seven cases: three pelvic and four perineal reconstructions.Our 66-year-old patient originally had an anterior resection for a Dukes’ B rectosigmoid adenocarcinoma followed by post-operative 5-fluorouracil and radiotherapy. He developed several radiation related complications including severe radiation enterocolitis, small bowel obstruction, ileal stricture and an enterovesical fistula. The latter two required small bowel resection and a diversion procedure respectively.en bloc excision of the neorectum, the rectal stump, the mesorectum, the bladder with a segment of diverted small bowel and the prostate. Both the end colostomy and ileal conduit were fashioned. His post-operative recovery was complicated by the development of a pelvic haematoma requiring incisional drainage via the perineum  shows no evidence of tumour recurrence or a keratinoma.Difficulties encountered particular to this case were a persistent and significant volume of dead space in the pelvic cavity, the continuity of this cavity with a large perineal defect and a progressive re-epithelialisation of the cavity walls within. The process of cavity wall re-epithelialisation has the potential to develop a keratinoma if allowed to proliferate. However, the exact incidence of this has not been reported in the literature. A keratinoma can grow slowly over time and, if it becomes infected, it is a potential source of overwhelming sepsis. Treatment is by excision. Surveillance CT will be required in this case to monitor for epithelial regrowth as well as for tumour recurrence.The large, pelvic dead space encountered was mainly contributed to by previous radiation enterocolitis with the resultant adherence of small bowel and omentum to the abdominal wall. This lack of descent prevented the required obliteration of the cavity. A combination of various disease states of the perineum, its adjacent orifices and dressing challenges make perineal healing an arduous task. This is further compounded when a perineal defect is in continuity with empty pelvic cavity, which is at risk of haematoma and seroma development.Reconstruction of the perineum and pelvis using microvascular transfer of the LD is a relatively recent development and is less commonly opted for if more local myocutaneous options are available. This is supported by a review of the literature, which found five articles (in English) describing three pelvic and four perineal reconstructions using this free flap.et al described its use in an early case of pelvic reconstruction in 1982.et al reported a perineal reconstruction for a complicated perineal wound following a proctectomy for Crohn’s disease.et al demonstrated a significant success rate of 18 cases of flap closure following APR; 3 of these were microvascular transfer of the LD.et al described the use of this flap in the reconstruction of a perianal wound in continuity with precoccygeal dead space following radiation associated infection after APR.Kraybill 3 and using the gracilis pedicle as the donor vessel, it provided an excellent size match for this defect.The preferred flaps for the reconstruction of the pelvis and perineum include the gracilis, bilateral gluteus maximus, rectus abdominis, anterolateral and posterolateral thigh flaps. In our case, due to the inaccessibility of these more commonly employed flaps, the LD free flap proved an excellent substitute. Together with a pedicle length of 13cm, an approximate volume of 300cm


Gable roof buildings are widely used in industrial buildings. Based on wind tunnel tests with rigid models, wind pressure distributions on gable roof buildings with different aspect ratios were measured simultaneously. Some characteristics of the measured wind pressure field on the surfaces of the models were analyzed, including mean wind pressure, fluctuating wind pressure, peak negative wind pressure, and characteristics of proper orthogonal decomposition results of the measured wind pressure field. The results show that extremely high local suctions often occur in the leading edges of longitudinal wall and windward roof, roof corner, and roof ridge which are the severe damaged locations under strong wind. The aspect ratio of building has a certain effect on the mean wind pressure coefficients, and the effect relates to wind attack angle. Compared with experimental results, the region division of roof corner and roof ridge from AIJ2004 is more reasonable than those from CECS102:2002 and MBMA2006.The contributions of the first several eigenvectors to the overall wind pressure distributions become much bigger. The investigation can offer some basic understanding for estimating wind load distribution on gable roof buildings and facilitate wind-resistant design of cladding components and their connections considering wind load path. Light-weight buildings with gable roof have been widely used in low-rise industrial buildings due to high degree of industrialization and rapid speed of construction; however, their relatively light dead load and flexibility make them most vulnerable to wind load which becomes a very important load type in structural design. In recent years, light-weight buildings with gable roof were usually damaged severely under strong wind, which caused huge economic losses.An accurate knowledge of wind pressure or their coefficients on the walls and roofs of buildings is essential to the wind-resistant design of structures. Holmes  investigIt is well known that the structural systems of such light-weight buildings with gable roof consist of portal or pin-jointed frames. The metal sheathings are attached to the roof purlins and the wall girts by the fasteners, which are fixed to these frames. Wind load path has significant effect on the effective wind loaded area of cladding components which are definitely not mentioned in current wind-resistant design, especially for the fasteners. The long-term objective of this study is to investigate how actual wind load is equivalent to extreme wind load on main structure, cladding components, and fasteners of light-weight steel structure considering the spatial correlation of wind pressure and wind load path in wind-resistant design.The present study, however, is only a preliminary study on gable roof buildings with emphasis on the understanding of wind pressure on gable roof buildings, through comparisons with existing results and relative wind load codes, to facilitate wind-resistant design of cladding components and their connections considering wind load path.The wind tunnel tests were carried out in the Boundary Layer Wind Tunnel at State Key Laboratory for Disaster Reduction in Civil Engineering at Tongji University. This wind tunnel has a working section of 15 m length, 3 m width, and 2.5 m height.Load Code for the Design of Building Structures (GB50009-2001) of China  is the spatial correlation matrix of fluctuating wind pressure, [Φ] is the eigenvector matrix, and [λ] is the eigenvalue matrix.The spatial correlation matrix of fluctuating wind pressure based on wind tunnel tests can be decomposed asThe orthogonal eigenvector group obtained from  can be rLocal high suctions often occur in the leading edges of longitudinal wall and windward roof, roof corner, and roof ridge, due to the separation of air flow and the formation of conical vortex in oblique wind, which are the severe damaged locations under strong wind. The aspect ratio of building has a certain effect on the mean wind pressure coefficients, and the effect relates to wind attack angle.The experimental shape coefficients appear higher than code values given by CECS102:2002 and MBMA2006 and relatively close to code values given by AIJ2004. Compared with experimental results, the region division of roof corner and roof ridge from AIJ2004 is more reasonable than those from CECS102:2002 and MBMA2006.Due to a good spatial correlation of wind pressure on the surface with edges and corners, the first mode makes a significant larger contribution to a global description of wind pressure distribution, derived from the proper orthogonal decomposition of the measured wind pressure field on gable roof building. The first several modes give a global description of wind pressure distribution on the model surface, while the other high-order modes just represent local distributions.The characteristics of wind pressure acting on the longitudinal walls and roofs of gable roof buildings with different aspect ratio, based on wind tunnel tests, have been described, including mean wind pressure, fluctuating wind pressure, and peak negative wind pressures, and compared with existing results. The characteristics of proper orthogonal decomposition on the building model are obtained based on wind pressure field data. The following conclusions may be made from the study.