Monocyte chemoattractant protein 3 as a mediator of fibrosis: Overexpression in systemic sclerosis and the type 1 tight-skin mouse

OBJECTIVE: To determine the gene-expression profile in dermal fibroblasts from type 1 tight-skin (Tsk1) mice, and to examine the expression and potential fibrotic activity of monocyte chemoattractant protein 3 (MCP-3) in Tsk1 mouse and human systemic sclerosis (SSc) skin. METHODS: Complementary DNA microarrays (Atlas 1.2) were used to compare Tsk1 fibroblasts with non-Tsk1 littermate cells at 10 days, 6 weeks, and 12 weeks of age. Expression of MCP-3 protein was assessed by Western blotting of fibroblast culture supernatants, and localized in the mouse and human skin biopsy samples by immunohistochemistry. Activation of collagen reporter genes by MCP-3 was explored in transgenic mouse fibroblasts and by transient transfection assays. RESULTS: MCP-3 was highly overexpressed by neonatal Tsk1 fibroblasts and by fibroblasts cultured from the lesional skin of patients with early-stage diffuse cutaneous SSc. Immunolocalization confirmed increased expression of MCP-3 in the dermis of 4 of 5 Tsk1 skin samples and 14 of 28 lesional SSc skin samples, compared with that in matched healthy mice (n = 5) and human controls (n = 11). Proalpha2(I) collagen promoter-reporter gene constructs were activated by MCP-3 in transgenic mice and by transient transfection assays. This response was maximal between 16 and 24 hours of culture and mediated via sequences within the proximal promoter. The effects of MCP-3 could be diminished by a neutralizing antibody to transforming growth factor beta. CONCLUSION: We demonstrate, for the first time, overexpression of MCP-3 in early-stage SSc and in Tsk1 skin, and suggest a novel role for this protein as a fibrotic mediator activating extracellular matrix gene expression in addition to promoting leukocyte trafficking. This chemokine may be an important early member of the cytokine cascade driving the pathogenesis of SSc.     

Metachronous Multiple Primary Malignant Neoplasms of the Stomach and the Breast: Report of Two Cases With Review of Literature

Multiple primary malignant neoplasm is the occurrence of a second primary malignancy in the same patient within 6 months of the detection of first primary (synchronous), or 6 months or more after primary detection (metachronous). Multiple primary malignant neoplasms are not very frequently encountered in clinical practice. The relative risk for a second primary malignancy increases by 1.111-fold every month from the detection of the first primary malignancy in any individual. We present 2 patients treated for carcinoma of the breast who developed a metachronous primary malignancy in the stomach to highlight the rare occurrence of multiple primary malignant neoplasms. These tumors were histologically dissimilar, with distinct immunohistochemical parameters. The importance lies in carefully identifying the second primary malignancies, not dismissing them as metastases, and treating them accordingly.Key words: Breast neoplasms, Stomach neoplasms, Neoplasms, Second primaryBreast cancer is the most common malignancy among women worldwide. With proper screening, earlier detection, and improved treatment, survival has greatly increased, with the result that there is now a large population of women with a present or past history of breast cancer. This has led to an increased detection of second primary malignancies among these women. The relative risk for a second primary malignancy increases by 1.111-fold every month from the detection of the first primary malignancy in any individual.¹ Several authors have reported on a lesion in the stomach being labeled as a second primary malignancy and subsequently found to be metastasis. When the primary breast tumor is positive for estrogen and progesterone receptors (ER/PRs) and the stomach tumor is ER/PR negative, the diagnosis is established easily.² However, studies have shown that some primary gastric cancers can have ER/PR positivity. Further, if the primary breast lesion is ER/PR negative, the same cannot be used as a marker. Here, we present 2 breast cancer patients who developed second primary malignancies in the stomach and the final diagnosis was established based on histopathology and immunohistochemistry.     

Giant Inguinoscrotal Hernia—Report of a Rare Case With Literature Review

Massive inguinoscrotal hernias extending below the midpoint of the inner thigh, in the standing position constitute giant inguinoscrotal hernias. We report a patient who presented with giant right inguinal hernia with bilateral hydrocele for 25 years. He had no cardiorespiratory illnesses. He was taken up for surgery under general anesthesia after preoperative respiratory exercises. Sliding hernia with entire greater omentum, small bowel, and appendix as contents was identified. Meshplasty after omentectomy with bilateral subtotal excision of sac, right orchidectomy, and scrotoplasty were done. Giant inguinoscrotal hernias pose significant problems while replacing bowel contents because of the increase in intraabdominal and intrathoracic pressures. Recurrence is another complication seen after successful surgical management. Various techniques such as preoperative pneumoperitoneum, debulking abdominal contents with extensive bowel resections, or omentectomy and phrenectomy have been tried. Postoperative elective ventilation is also needed in many cases. We describe simple reduction with omentectomy as a viable technique in this patient. He did not need elective ventilation due to preoperative respiratory exercises and preparation and review of the literature.Key words: Debulking, Giant inguinoscrotal hernia, Massive inguinoscrotal hernia, Phrenectomy, VentilationGiant inguinoscrotal hernias are defined as those extending below the midpoint of the inner thigh, in the standing position.¹ These hernias are rare and usually the result of neglect or fear of surgical procedures and are prevalent in the rural population.² These massive hernias pose significant problems resulting from cardiorespiratory compromise following sudden increase in intra-abdominal pressure during replacement of herniated viscera.³ In order to circumvent these complications, techniques such as debulking, phrenectomy, and progressive pneumoperitoneum have been described.³ Here, we present a patient with giant inguinoscrotal hernia where simple reduction with omentectomy was successful, and we review the literature.     

Multiple myeloma: 2014 Update on diagnosis,risk‐stratification,and management

Disease overview : Multiple myeloma accounts for approximately 10% of hematologic malignancies. Diagnosis : The diagnosis requires 10% or more clonal plasma cells on bone marrow examination or a biopsy proven plasmacytoma plus evidence of associated end‐organ damage. If end‐organ damage is not present, the presence of 60% or more clonal plasma cells in the marrow is also considered as myeloma. Risk stratification : In the absence of concurrent trisomies, patients with 17p deletion, t(14;16), and t(14;20) are considered to have high‐risk myeloma. Patients with t(4;14) translocation are considered intermediate‐risk. All others are considered as standard‐risk. Risk‐adapted intial therapy : Standard‐risk patients can be treated with lenalidomide plus low‐dose dexamethasone (Rd), or a bortezomib‐containing triplet such as bortezomib, cyclophosphamide, dexamethasone (VCD). Intermediate‐risk and high‐risk patients require a bortezomib‐based triplet regimen. In eligible patients, initial therapy is given for approximately 4 months followed by autologous stem cell transplantation (ASCT). Standard risk patients can opt for delayed ASCT if stem cells can be cryopreserved. In patients who are not candidates for transplant, initial therapy is given for approximately 12 to 18 months. Maintenance therapy : After initial therapy, lenalidomide maintenance is considered for standard risk patients who are not in very good partial response or better, while maintenance with a bortezomib‐based regimen should be considered in patients with intermediate or high risk myeloma. Management of refractory disease : Patients with indolent relapse can be treated first with 2‐drug or 3‐drug combinations. Patients with more aggressive relapse often require therapy with a combination of multiple active agents. Am. J. Hematol. 89:998–1009, 2014. © 2014 Wiley Periodicals, Inc.     

Haplotype-based study of the association of alcohol and acetaldehyde-metabolising genes with alcohol dependence (with or without comorbid anxiety symptoms) in a Cape Mixed Ancestry population

Alcohol dependence (AD) has a large heritable component. Genetic variation in genes involved in the absorption and elimination of ethanol have been associated with AD. However, some of these polymorphisms are not present in an African population. Previous studies have reported that a type of AD which is characterized by anxious behaviour may be a genetically specific subtype of AD. We investigated whether variation in genes encoding cytochrome P450 2E1 (CYP2E1) or acetaldehyde-metabolising enzymes (ALDH1A1, ALDH2) might alter the risk of AD, with and without symptoms of anxiety, in a Cape population with mixed ancestry. Eighty case control pairs (one with AD, one without AD) were recruited and individually matched for potential confounders. Genotype data were available for 29 single-nucleotide polymorphisms (SNPs) across the three genes. Linkage disequilibrium D′ values were evaluated for all pairwise comparisons. Allele and haplotype frequencies were compared between cases and controls using a χ ² test. The ACAG haplotype in block 4 of the ALDH1A1 gene provided evidence of an association with AD (p?=?0.03) and weak evidence of an association with AD without symptoms of anxiety (p?=?0.06). When a genetic score was constructed using SNPs showing nominal evidence of association with AD, every extra risk allele increased the odds of AD by 35 % (OR 1.35, 95%CI 1.08, 1.68, p?=?0.008) and the odds of having AD with anxiety symptoms increased by 53 % (OR 1.53, 95%CI 1.14, 2.05, p?=?0.004). Although our results are supported by previous studies in other populations, they must be interpreted with caution due to the small sample size and the potential influence of population stratification.     

Refining amyloid complete hematological response: Quantitative serum free light chains superior to ratio

Response assessment in light chain (AL) amyloidosis is based on serum and urine monoclonal protein studies. Newly diagnosed patients (n = 373) who achieved very good partial response or complete response (CR) to first line therapy were assessed for the survival impact of each of the monoclonal protein studies. At end of therapy (EOT), negative serum/urine immunofixation (IFE) was achieved in 61% of patients, 72% achieved normal serum free light chain ratio (sFLCR), and the median involved free light chain (iFLC) and difference between involved to uninvolved light chain (dFLC) were 17 mg/L and 5 mg/L, respectively. Overall, 46% of patients achieved a CR at EOT. At EOT, iFLC ≤20 mg/L and dFLC ≤10 mg/L were additive in survival discrimination to negative serum/urine IFE and were independent predictors of overall survival. In contrast, normalization of sFLCR did not add survival discrimination to serum/urine IFE and was not independent predictor of survival. We propose a new definition for hematological CR to include serum/urine IFE negativity plus iFLC ≤20 mg/L or dFLC ≤10 mg/L, instead of the current definition of serum/urine IFE negativity and normal sFLCR. Complete response using dFLC ≤10 mg/L had the best performance in those with significant renal dysfunction and by light chain isotype, making it the preferred partner to IFE. Validation of these results in a multicenter cohort is warranted.     

Greater Arch Injuries

Dislocations and fracture dislocations of carpal bones are uncommon injuries which invariably poses challenges in the management. Perilunate fracture dislocations are the combination of ligamentous and osseous injury that involve the “greater arc” of the perilunate associated instability. Despite their severity, these injuries often go unrecognized in the emergency department leading to delayed diagnosis and treatment. A Prospective study was done from June 2008 to December 2013 in 15 cases of complex wrist injuries which included of greater arch injuries, perilunate fracture dislocation and one dorsal dislocation of Scaphoid. 10 cases of perilunate fracture dislocation underwent open reduction and internal fixation with Herbert screw and k-wire, 4 cases of greater arch injury underwent closed reduction and kwire fixation and one case of neglected dorsal dislocation underwent proximal row carpectomy. One patient had Sudecks osteodystrophy 1 had Scaphoid nonunion and 6 had median nerve compression. Overall outcome according to Mayo wrist score was 53 % excellent, 33 % good and 14 % fair. Greater arch injuries are difficult to treat because injuries to many ligaments are involved and failure to recognize early leads to persistent pain, disability and early onset of arthritis. Prompt recognition requires CT scan and MRI. Management requires reduction and multiple K-Wiring according to merits of the case.     

Establishing postprandial bio-equivalency and IVIVC for generic metformin sustained release small sized tablets

The objective of current study was to develop metformin hydrochloride modified release small sized tablets, and to evaluate its bioequivalence when compared with the reference product (Glucophage^® SR). The physicochemical properties of the formulated and reference tablets were determined and compared. The in vitro dissolution profiles of formulated tablets were obtained using bio-relevant media and IVIVC was established. Bioequivalence investigation was carried out in 32 healthy male volunteers who received a single dose 1,000 mg of both test and reference products in a randomized two-way crossover design in postprandial conditions. After dosing, serial blood samples were collected for a period of 48 h. Metformin concentration was assayed by using a validated LC–MS/MS method. The log-transformed C_max and AUC were statistically compared by analysis of variance, and the 90 % confidence intervals (CI) of the ratio of the log-transformed C_max and AUC between the most promising developed formulation and the reference product were determined. It was deduced that the dissolution rate profile of the formulated modified release small sized tablets was similar to the reference product employed in the study. Their similarity and difference factors were found to be well within the established limits. In the bioequivalence study, the difference in C_max, AUC_last and AUC_inf between the test and reference product was not statistically significant, with the 90 % CI of 100.73–116.20, 86.16–97.37 and 87.12–96.99 %, respectively. The results suggested that the metformin small tablets formulated with reduced quantity of controlled release polymer were found to be bioequivalent in the postprandial state. For these small tablets, pH 5.5 acetate buffer as a bio-relevant dissolution media for the development of IVIVC.